Organoboron compounds and methods of making organoboron compounds

ABSTRACT

Embodiments of the present disclosure provide for methods of making an organoboron compound, organoboron compounds, and the like.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/296,456 entitled “ORGANOBORON COMPOUNDS AND METHODS OF MAKINGORGANOBORON COMPOUNDS”, filed on Oct. 18, 2016. U.S. patent applicationSer. No. 15/296,456 is a continuation of U.S. patent application Ser.No. 14/941,880 entitled “ORGANOBORON COMPOUNDS AND METHODS OF MAKINGORGANOBORON COMPOUNDS” filed on Nov. 16, 2015, now issued as U.S. Pat.No. 9,512,147. U.S. patent application Ser. No. 14/941,880 is acontinuation-in-part of U.S. patent application Ser. No. 14/303,684entitled “ORGANOBORON COMPOUNDS AND METHODS OF MAKING ORGANOBORONCOMPOUNDS,” now issued as U.S. Pat. No. 9,238,661, filed on Jun. 13,2014, which claims priority to U.S. Provisional Application No.61/906,040 entitled “BORONIC COMPOUNDS AND METHODS OF MAKING BORONICCOMPOUNDS,” filed on Nov. 19, 2013 and U.S. Provisional PatentApplication No. 61/836,391 entitled “BORONIC COMPOUNDS AND METHODS OFMAKING BORONIC COMPOUNDS,” filed on Jun. 18, 2013, each of which isentirely incorporated herein by reference.

U.S. patent application Ser. No. 14/941,880, filed on Nov. 16, 2015, nowissued as U.S. Pat. No. 9,512,147, also claims priority to U.S.Provisional Application No. 62/198,410 entitled “BORONIC COMPOUNDS ANDMETHODS OF MAKING BORONIC COMPOUNDS,” filed on Jul. 29, 2015 and U.S.Provisional Application No. 62/200,354 entitled “BORONIC COMPOUNDS ANDMETHODS OF MAKING BORONIC COMPOUNDS,” filed on Aug. 3, 2015, each ofwhich is entirely incorporated herein by reference.

FEDERAL SPONSORSHIP

This invention was made with Government support under Contract/Grant No.1R01GM098512-01, awarded by the National Institutes of Health. TheGovernment has certain rights in this invention.

BACKGROUND

Since the initial report of a hydroboration reaction, the addition ofH—B bonds to alkynes has become a widely-used reaction in organicsynthesis. The resulting vinyl boranes are versatile intermediates foroxidation, copper-catalyzed conjugate addition, and Suzukicross-coupling reactions. However, despite the widespread utility of thehydroboration reaction and development of many related X—B bond additionreactions (where X is a non-hydrogen atom), addition by some other typesof boron bonds has not been reported.

SUMMARY

Embodiments of the present disclosure provide for methods of making anorganoboron compound, organoboron compounds, and the like.

An exemplary embodiment of the present disclosure includes methods,among others, such as those described in the schemes illustrated inFIGS. 1.1A-1.1H and FIGS. 6.14-6.41 and described in the claims.

An exemplary embodiment of the present disclosure includes, amongothers, a composition, comprising: compounds such as those described inFIGS. 6.1-6.13 as well as the products shown in FIGS. 1.1A-1.1H, anddescribed in the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Further aspects of the present disclosure will be more readilyappreciated upon review of the detailed description of its variousembodiments, described below, when taken in conjunction with theaccompanying drawings.

FIG. 1.1A illustrates Schemes (1) to (3).

FIG. 1.1B illustrates Schemes (4) to (6).

FIG. 1.1C illustrates Schemes (7) to (9).

FIG. 1.1D illustrates Schemes (10) to (12).

FIG. 1.1E illustrates Schemes (13) to (15).

FIG. 1.1F illustrates Schemes (16) to (18).

FIG. 1.1G illustrates Schemes (19) to (22).

FIG. 1.1H illustrates Schemes (23) to (25).

FIG. 1.2 illustrates embodiments of various organoboron compounds madeusing embodiments of the present disclosure.

FIG. 1.3 illustrates an embodiment of a reaction scheme to form anorganoboron compound.

FIG. 1.4 illustrates an embodiment of a reaction scheme to form anorganoboron compound.

FIG. 1.5 illustrates embodiments of a reaction scheme to form anorganoboron compound and various organoboron compounds.

FIGS. 2.1A and 2.1B illustrates examples of related B—X bond additionreactivity and an embodiment of a method of the present disclosure.

FIG. 2.2 illustrates a ball and stick figure of an organotrifluoroboratecompound.

FIG. 2.3 illustrates an embodiment of various compounds and thecorresponding methods.

FIG. 3.1 illustrates an embodiment of a method of making organoboroncompounds.

FIG. 4.1 illustrates an oxyboration method of the present disclosure.

FIGS. 5.1A-C illustrate the addition of B-E σ bonds across C—C π bonds.

FIG. 6.1 illustrates the products of Schemes (26) to (29).

FIG. 6.2 illustrates the products of Schemes (30) to (39).

FIG. 6.3 illustrates the products of Schemes (40) to (45).

FIG. 6.4 illustrates the products of Schemes (46) to (49).

FIG. 6.5 illustrates the products of Schemes (50) to (56).

FIG. 6.6 illustrates the products of Schemes (57) to (66).

FIG. 6.7 illustrates the products of Schemes (67) to (74).

FIG. 6.8 illustrates the products of Schemes (75) to (82).

FIG. 6.9 illustrates the products of Schemes (83) to (88).

FIG. 6.10 illustrates the products of Schemes (89) to (97).

FIG. 6.11 illustrates the products of Schemes (98) to (106).

FIG. 6.12 illustrates the products of Schemes (107) to (115).

FIG. 6.13 illustrates the products of Schemes (116) to (121).

FIG. 6.14 illustrates Schemes (26) to (29).

FIG. 6.15 illustrates Schemes (30) to (33).

FIG. 6.16 illustrates Schemes (34) to (37).

FIG. 6.17 illustrates Schemes (38) to (41).

FIG. 6.18 illustrates Schemes (42) to (45).

FIG. 6.19 illustrates Schemes (46) to (47).

FIG. 6.20 illustrates Schemes (48) to (51).

FIG. 6.21 illustrates Schemes (52) to (56).

FIG. 6.22 illustrates Schemes (57) to (62).

FIG. 6.23 illustrates Schemes (63) to (66).

FIG. 6.24 illustrates Schemes (67) to (70).

FIG. 6.25 illustrates Schemes (71) to (74).

FIG. 6.26 illustrates Schemes (75) to (79).

FIG. 6.27 illustrates Schemes (80) to (82).

FIG. 6.28 illustrates Schemes (83) to (85).

FIG. 6.29 illustrates Schemes (86) to (88).

FIG. 6.30 illustrates Schemes (89) to (91).

FIG. 6.31 illustrates Schemes (92) to (94).

FIG. 6.32 illustrates Schemes (95) to (97).

FIG. 6.33 illustrates Schemes (98) to (100).

FIG. 6.34 illustrates Schemes (101) to (103).

FIG. 6.35 illustrates Schemes (104) to (106).

FIG. 6.36 illustrates Schemes (107) to (109).

FIG. 6.37 illustrates Schemes (110) to (112).

FIG. 6.38 illustrates Schemes (113) to (115).

FIG. 6.39 illustrates Schemes (116) to (118).

FIG. 6.40 illustrates Schemes (119) to (121).

FIG. 6.41 illustrates Schemes (122) to (123).

FIG. 7.1 illustrates organogold-to-boron transmetalation via ion pair asshown in Scheme 3, Example 4.

DETAILED DESCRIPTION

Before the present disclosure is described in greater detail, it is tobe understood that this disclosure is not limited to particularembodiments described, as such may, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting, since the scope of the present disclosure will be limited onlyby the appended claims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit (unlessthe context clearly dictates otherwise), between the upper and lowerlimit of that range, and any other stated or intervening value in thatstated range, is encompassed within the disclosure. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges and are also encompassed within the disclosure, subjectto any specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the disclosure.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this disclosure belongs. Although any methods andmaterials similar or equivalent to those described herein can also beused in the practice or testing of the present disclosure, the preferredmethods and materials are now described.

As will be apparent to those of skill in the art upon reading thisdisclosure, each of the individual embodiments described and illustratedherein has discrete components and features which may be readilyseparated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the presentdisclosure. Any recited method can be carried out in the order of eventsrecited or in any other order that is logically possible.

Embodiments of the present disclosure will employ, unless otherwiseindicated, techniques of chemistry, synthetic organic chemistry, and thelike, which are within the skill of the art. Such techniques areexplained fully in the literature.

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how toperform the methods and use the compositions and compounds disclosed andclaimed herein. Efforts have been made to ensure accuracy with respectto numbers (e.g., amounts, temperature, etc.), but some errors anddeviations should be accounted for. Unless indicated otherwise, partsare parts by weight, temperature is in ° C., and pressure is in bar.Standard temperature and pressure are defined as 0° C. and 1 bar.

Before the embodiments of the present disclosure are described indetail, it is to be understood that, unless otherwise indicated, thepresent disclosure is not limited to particular materials, reagents,reaction materials, manufacturing processes, or the like, as such canvary. It is also to be understood that the terminology used herein isfor purposes of describing particular embodiments only, and is notintended to be limiting. It is also possible in the present disclosurethat steps can be executed in different sequence where this is logicallypossible. Different regiochemistry and stereochemistry is also possible,such as products of syn or anti addition could be both possible even ifonly one is drawn in an embodiment.

It must be noted that, as used in the specification and the appendedclaims, the singular forms “a,” “an,” and “the” include plural referentsunless the context clearly dictates otherwise. Thus, for example,reference to “a support” includes a plurality of supports. In thisspecification and in the claims that follow, reference will be made to anumber of terms that shall be defined to have the following meaningsunless a contrary intention is apparent.

Definitions

The term “substituted” refers to any one or more hydrogens on thedesignated atom (e.g., a carbon atom) that can be replaced with aselection from the indicated group, provided that the designated atom'snormal valence is not exceeded, and that the substitution results in astable compound. In an embodiment, substituted can refer to substitutionof one or more Hs with CF₃, CN, NO₂, a halogen, an alkyl group (e.g., C1to C4), an carboxy group (e.g., —C(O)—O—R″, where R″ can be H or analkyl group), an amide group (e.g., R″C(O)—N(R″)—″, where each R″ canindependently be H or an alkyl group), a thiol group (e.g., —SH), athioether (e.g., —S—R, where R can be an alkyl group), an alcohol group(e.g., —OH), a carbonyl group (e.g., R″C(O)—, where R″ can be H or analkyl group), an alkoxy group (e.g., —O—R″, where R″ can be H or analkyl group), and an amine group (—NR″R″, where each R″ canindependently be H or an alkyl group).

As used herein, “alkyl” or “alkyl group” refers to a linear or branchedsaturated and unsaturated aliphatic cyclic or acyclic hydrocarbon.Examples of alkyl include, but are not limited to, methyl, ethyl, vinyl,allyl, propyl, butyl, trifluoromethyl, and pentafluoroethyl.

The term “substituted,” as in “substituted alkyl”, “substituted aryl,”“substituted heteroaryl” and the like, in an embodiment can mean thatthe substituted group may contain in place of one or more hydrogens agroup such as alkyl, hydroxy, amino, nitro, halo, trifluoromethyl,cyano, —NH(lower alkyl), —N(lower alkyl)₂, lower alkoxy, loweralkylthio, carbonyl, or carboxy, and thus embraces the terms haloalkyl,alkoxy, fluorobenzyl, and the sulfur and phosphorous containingsubstitutions referred to below, where lower refers to 1 to 6 carbonsatoms, for example.

As used herein, “halo”, “halogen”, or “halogen radical” refers to afluorine, chlorine, bromine, and iodine, and radicals thereof. Further,when used in compound words, such as “haloalkyl” or “haloalkenyl”,“halo” refers to an alkyl or alkenyl radical in which one or morehydrogens are substituted by halogen radicals. Examples of haloalkylinclude, but are not limited to, trifluoromethyl, trichloromethyl,pentafluoroethyl, and pentachloroethyl.

The term “carbonyl” refers to functional groups such as an amide, ester,ketone, or aldehyde, where each can be substituted or unsubstituted.

The term “carboxy” refers to a subset of carbonyl functional groups suchas an amide, carboxylic acid, or ester, where each can be substituted orunsubstituted.

The term “carbocycles” refers to a monocyclic or multicyclic ring systemof about 5 to about 14 carbon atoms, preferably of about 6 to about 10carbon atoms. In an embodiment, carbocycle can refer to an aryl group.Exemplary carbocycles can refer to functional groups such as phenyl andnaphthyl. Carbocycles include substituted or unsubstituted carbocycles.

The term “aryl” as used herein, refers to an aromatic monocyclic ormulticyclic ring system of about 6 to about 14 carbon atoms, preferablyof about 6 to about 10 carbon atoms, substituted or unsubstituted.Exemplary aryl groups include phenyl or naphthyl, or phenyl substitutedor naphthyl substituted.

The term “heterocycle” is used herein to denote a ring or fused ringstructure of carbon atoms with one or more non-carbon atoms, such asoxygen, nitrogen, and sulfur, in the ring or in one or more of the ringsin fused ring structures, substituted or unsubstituted. In anembodiment, heterocycle can refer to a heteroaryl group. Preferredexamples are furan, pyrrole, thiophene, benzofuran, indole,benzothiophene, pyridine, quinoline, isoquinoline, oxazole, benzoxazole,isoxazole, triazole, pyrroline, pyrrolidine, imidazole, imidazoline,pyrazole, pyran, piperidine, dioxane, morpholine, pyrimidine,pyridazine, pyrazine, indolizidine, isoindole, indoline, benzimidazole,carbazole, thiazole, each of which can be substituted or unsubstituted.

The term “heteroaryl” is used herein to denote an aromatic ring or fusedring structure of carbon atoms with one or more non-carbon atoms, suchas oxygen, nitrogen, and sulfur, in the ring or in one or more of therings in fused ring structures, substituted or unsubstituted. Examplesare furanyl, pyranyl, thienyl, imidazyl, pyrrolyl, pyridyl, pyrazolyl,pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalyl, andquinazolinyl. Preferred examples are furanyl, imidazyl, pyranyl,pyrrolyl, and pyridyl.

The term “biaryl” refers to an aryl, as defined above, where two arylgroups are joined by a direct bond or through an intervening alkylgroup, preferably a lower alkyl group, substituted or unsubstituted.

The term “fused aryl” refers to a multicyclic ring system as included inthe term “aryl,” and includes aryl groups and heteroaryl groups that arecondensed, substituted or unsubstituted. Examples are naphthyl, anthryland phenanthryl. The bonds can be attached to any of the rings.

General Discussion

Embodiments of the present disclosure provide for methods of making anorganoboron compound, organoboron compounds, and the like. An advantageof an exemplary method (e.g., oxyboration, carboboration, allylboration,amidoboration, thioamidoboration, amidinoboration, alkoxyboration,aminoboration, or thioboration) of the present disclosure is thatorganoboron compounds can be made that could not be made previously orthe synthesis is much more complicated. In addition, exemplaryembodiments of the method can be performed in a few steps in a “one-pot”synthesis using temperature or a catalyst to drive the reaction.

FIGS. 1.1A-1.1H and 6.1-6.13 illustrate products formed by reactionschemes (1)-(123).

In an exemplary embodiment, a method of the synthesis includes thereactions shown in FIG. 1.1A (Schemes 1-3), FIG. 1.1B (Schemes 4-6),FIG. 1.1C (Schemes 7-9), FIG. 1.1D (Schemes 10-12), FIG. 1.1E (Schemes13-15), FIG. 1.1F (Schemes 16-18), FIG. 1.1G (Schemes 19-22), FIG. 1.1H(Schemes 23-25), FIG. 6.14 (Schemes 26 to 29), FIG. 6.15 (Schemes 30 to33), FIG. 6.16 (Schemes 34 to 37), FIG. 6.17 (Schemes 38 to 41), FIG.6.18 (Schemes 42 to 45), FIG. 6.19 (Schemes 46 to 47), FIG. 6.20(Schemes 48 to 51), FIG. 6.21 (Schemes 52 to 56), FIG. 6.22 (Schemes 57to 62), FIG. 6.23 (Schemes 63 to 66), FIG. 6.24 (Schemes 67 to 70), FIG.6.25 (Schemes 71 to 74), FIG. 6.26 (Schemes 75 to 79), FIG. 6.27(Schemes 80 to 82), FIG. 6.28 (Schemes 83 to 85), FIG. 6.29 Schemes (86)to (88), FIG. 6.30 (Schemes 89 to 91), FIG. 6.31 (Schemes 92 to 94),FIG. 6.32 (Schemes 95 to 97), FIG. 6.33 (Schemes 98 to 100), FIG. 6.34(Schemes 101 to 103), FIG. 6.35 (Schemes 104 to 106), FIG. 6.36 (Schemes107 to 109), FIG. 6.37 (Schemes 110 to 112), FIG. 6.38 (Schemes 113 to115), FIG. 6.39 (Schemes 116 to 118), FIG. 6.40 (Schemes 119 to 121),FIG. 6.41 (Schemes 122 to 123).

In general, X, X¹, X², X³, Y, [B], (B′), R, R¹, R², R³, R⁴, R⁵ R⁶, R⁷,and R⁸ in the reactions scheme and organoboron compounds are describedbelow. In an embodiment, n, y, p, and q can be 0 to 10, 0 to 6, 0 to 3,1 to 10, 1 to 6, or 1 to 3, or any integer range disclosed therein(e.g., 2 to 8 or 2 to 4).

In an embodiment, [B] can be BX² _((1 or2)), where X² can independentlyselected from: catecholate, pinacolate, ethylene glycolate,1,3-propanediolate, N-methyliminodiacetate, 2,2′-azanediyldiethanolate,fluoride, chloride, bromide, hydrogen, hydroxide, acetate,9-Borabicyclo[3.3.1]nonane (9-BBN), diisopinocampheyl (Ipc),1,8-diaminonaphthalene, or similar compounds, each of which can besubstituted or unsubstituted. It should be noted that (B′) is used toillustrate that one or more groups can be substituted to obtain a morestable product. In this regard, (B′) can be the same as [B] or can havea group (X or X²) that is more accommodating to the cyclizationreaction, where the group can be substituted to form the productdepending upon the stability or other considerations of the product.

In an embodiment, [B] of [B]—X can be BX² _((1 or 2)), where X² can becatecholate, pinacolate, ethylene glycolate, 1,3-propanediolate,N-methyliminodiacetate, 2,2′-azanediyldiethanolate, fluoride, chloride,bromide, hydrogen, hydroxide, acetate, 9-Borabicyclo[3.3.1]nonane(9-BBN), diisopinocampheyl (Ipc), 1,8-diaminonaphthalene, or similarcompounds, each of which can be substituted or unsubstituted. In anembodiment, X can be a H, halide, acetoxy (OAc), trifluoroacetate (TFA),tosylate (OTs), mesylate (OMs), or triflate (OTf).

In an embodiment, Y can be CH₂, CRH, CR₂, NR, O, S, PR or SiR₂, where Rcan be H, a carbonyl functional group (substituted or unsubstituted)(e.g., 1 to 6 carbons), a carboxy functional group (substituted orunsubstituted) (e.g., 2 to 6 carbons), a carbocycle group (substitutedor unsubstituted) (e.g., 4 to 8 carbons), a heterocycle (substituted orunsubstituted) (e.g., 4 to 8 carbons), a halide (fluoride, chloride,bromide, iodide), and an alkyl group (substituted or unsubstituted)(e.g., 1 to 6 carbons).

In an embodiment, the carbonyl functional group can be a moiety selectedfrom: a ketone, or an aldehyde, each of which can be substituted orunsubstituted.

In an embodiment, the carboxy functional group can be a moiety selectedfrom: an ester, a carboxylic acid, or an amide, each of which can besubstituted or unsubstituted.

In an embodiment, the carbocycle or heterocycle group can be a moietyselected from: phenyl, naphthyl, furan, pyrrole, thiophene, benzofuran,indole, benzothiophene, pyridine, quinoline, isoquinoline, oxazole,benzoxazole, isoxazole, triazole, pyrroline, pyrrolidine, imidazole,imidazoline, pyrazole, pyran, piperidine, dioxane, morpholine,pyrimidine, pyridazine, pyrazine, indolizidine, isoindole, indoline,benzimidazole, or carbazole, thiazole, each of which can be substitutedor unsubstituted.

In an embodiment, the alkyl group can be a C1 to C10 hydrocarbon. Forexample the alkyl group can be: methyl, ethyl, vinyl, allyl, propyl,butyl, trifluoromethyl, or pentafluoroethyl, each of which can besubstituted or unsubstituted.

In an embodiment, R can be H, a carbonyl functional group (substitutedor unsubstituted) such as a C1 to C6 ketone, a C3 to C6 ketone, a C2 toC6 carboxylic acid, a C3 to C6 ester, a C3 to C6 amide, a C4 to C8carbocycle group (substituted or unsubstituted), a C4 to C8 heterocycle(substituted or unsubstituted), fluoride, chloride, bromide, iodide, anda C1 to C6 alkyl group (substituted or unsubstituted).

In an embodiment, each of R, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, or R⁸ (as wellas other none-defined R groups), can independently be selected from: H,a carbonyl functional group (substituted or unsubstituted), a carbocyclegroup (substituted or unsubstituted), a heterocycle (substituted orunsubstituted), a halide (fluoride, chloride, bromide, iodide), an alkylgroup (cyclic or acyclic; substituted or unsubstituted), an alkenylgroup (cyclic or acyclic; substituted or unsubstituted), CF₃, CN, NO₂,an aryl group (substituted or unsubstituted), a heteroaryl group(substituted or unsubstituted), a sulfonyl group, a boryl group, anether group, a thioether group, a silyl group, an ester group, an amidegroup, an alkoxy group, a thiol group, an alcohol group, or an aminegroup. In an embodiment, each of R, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, or R⁸(as well as other yet defined R groups), can independently be selectedfrom: H, a C1 to C6 carbonyl functional group (substituted orunsubstituted), a C4 to C8 carbocycle group (substituted orunsubstituted), a C4 to C8 heterocycle (substituted or unsubstituted),fluoride, chloride, bromide, iodide, a C1 to C8 alkyl group (cyclic oracyclic; substituted or unsubstituted), a C2 to C8 alkenyl group (cyclicor acyclic; substituted or unsubstituted). Any and all individualcombinations of moieties of R, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and/or R⁸ areintended to be covered even if not specifically recited (e.g., R¹ is acarbonyl functional group, R² is a hydrogen, R³ is a heterocycle; R¹ isa hydrogen, R² is a carbocycle group, R³ is a heterocycle; R¹ is achloride, R² is a alkyl group, R³ is a heterocycle; and so on).

In an embodiment, adjacent R groups (e.g., R¹, R², R³, R⁴, R⁵, R⁶, R⁷,and/or R⁸, specifically the pair of R¹ and R²) together with the carbonatoms they are attached to, can form a cyclic moiety (e.g., C1 to C10,aromatic or non-aromatic (e.g., hetero or nonhetero)). In an embodiment,one or more R³, R⁴, R⁵, R⁶, and R⁷ moieties, where attached to a cyclicmoiety, can be attached to the ring, where if more than one R³, R⁴, R⁵,R⁶, and/or R⁷ moiety is present, each moiety can be independentlyselected. In embodiments where only one R group (e.g., R⁶ and R⁷) isattached to the ring, that R group represents one or multiple R groupsthat can be attached to the ring, where each R group is independentlyselected.

In embodiments having a “curved line” between groups such as R groups(e.g., R¹ and R²), the curved line can represent a carbon chain((CH₂)_(q), where q can be 0 to 10) that can include zero or moreheteroatoms (e.g., (CH₂)_(q)O(CH₂)_(q) or (CH₂)_(q)NH(CH₂)_(q))).

In an embodiment, X can be O, S, or —C(O)O—. —C(O)O— can be present in aring so that the ring is a heterocyclic ring. In an embodiment X is O.In an embodiment X is S.

In an embodiment, Y can be NR, O, S, SiR², or CR⁷R⁸. In an embodiment Yis NR. In an embodiment Y is O. In an embodiment Y is S. In anembodiment Y is SiR². In an embodiment Y is CR⁷R⁸.

In an embodiment, X¹ can be O, NR, S, or CR¹R², where each of R, R¹, R²,is independently selected from: H, a carbonyl functional group (e.g. C1to C6), a carbocycle group (e.g. C4 to C8), a heterocycle (e.g. C4 toC8), a halide, or an alkyl group (e.g. C1 to C6), where, optionally,each can be substituted or unsubstituted.

Any and all individual combinations of moieties of R, R¹, R², R³, R⁴,R⁵, R⁶, R⁷, R⁸, Y, [B], (B′), X¹, X², X³, and/or X⁴, are intended to becovered by the structures provided herein even if the specificcombination is not recited. Each and every combination of R, R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, Y, [B], (B′), X, X¹, X², X³, and/or X⁴ has not beenindividually provided for sake of clarity.

In an embodiment, the methods of making an organoboron compound can usea catalyst or reagent to produce the organoboron compound products. Inan embodiment the catalyst can include a metal catalyst such as a Lewisacid metal catalyst or another reagent or mediator that includes ametal. In general, the catalyst can include a metal (M) such as atransition metal salt (e.g., Cu, Ag, Au, Ni, Pd, Pt, In, Co, Rh, Ir, Ga,and Fe). In an embodiment, the metal can be supported by ligands such asphosphine oxides, aryl phosphines, alkyl phosphines,1,10-phenanthroline, AsR3, (R)-Binaphane, dialkyl monoaryl phosphines,or N-heterocyclic carbene ligands. The counter anion can include anionssuch as trifluoroacetate, tosylate, mesylate,bis(trifluoromethylsulfonyl)amide, triflate, perchlorate,tetrafluoroborate, hexafluorophosphate,tetrakis(pentafluorophenyl)borate, acetate, halides,tetrakis(3,5-bis(trifluoromethyl)phenyl)borate.

In an embodiment, the catalyst can be of the form L_(n)-M-X_(y), where Lcan be selected from P(OAr)₃

PAr₃ (e.g., PPh₃), PR₃ (e.g., P(tBu)₃), PArR₂,

PAr₂R, and NHC ligands (e.g., IMes, IPr, SIMes, SIPr,1,10-phenanthroline, AsR3, (R)-Binanphane), M can be selected from Cu,Ag, Au, Ni, Pd, Pt, In, Co, Rh, Ir, Ga, Fe, and the like, and X can beselected from TFA, NTf₂, OTf, OTs, OMs, ClO₄, BF₄, PF₆, SbF₆, B(C₆F₅)₄,OAc, halides, and

In particular, the catalyst can be of the form LMX, where L can be IPr(NHC ligands), PPh₃, P(Ar)₃, P(alkyl)₃, 1,10-phenanthroline, AsR₃,(R)-Binaphane, or include no ligand, M can be selected from Au, Cu, andAg, and X can be selected from TFA, OTf, OTs, NTf₂, OAc, BF₄, SbF₆,ClO₄, F, Cl, Br, I, BArF ([B[3,5-(CF₃)₂C₆H₃]₄], and B(C₆F₅)₄). Inaddition, the catalyst can be of the form L_(n)MX₂, where n is 0, 1, or2, L can be selected from IPr (NHC ligands), PPh₃, P(Ar)₃, P(alkyl)₃,1,10-phenanthroline, AsR₃, (R)-Binaphane, M can be selected from Cu, Pd,Fe, Ni, and Pt, and X can be selected from TFA, OTf, OTs, NTf₂, OAc,BF₄, SbF₆, ClO₄, F, Cl, Br, I, BArF ([B[3,5-(CF₃)₂C₆H₃]₄], or B(C₆F₅)₄⁻). Furthermore, the catalyst can be L_(n)MX₃, where n can be 1 or 3, Lcan be selected from IPr (NHC ligands), PPh₃, P(Ar)₃, P(alkyl)₃,1,10-phenanthroline, AsR₃, and (R)-Binaphane, M can be selected from Au,Fe, Ag, In, Ga, and Sn, and X can be selected from TFA, OTf, OTs, NTf₂,OAc, BF₄, SbF₆, ClO₄, F, Cl, Br, I, BArF ([B[3,5-(CF₃)₂C₆H₃]₄],B(C₆F₅)₄), EtAlCl₂, and B(C₆F₅)₃. In an embodiment, the catalyst caninclude IPrAuTFA, IPrAuOTs, IPrAuOH, IPrAuCl, IPrAuCl/NaTFA, CuOTf, CuI,CuTFA, IPrCuCl, IPrAuCl/AgOTf, IPrCuCl/AgTFA, IPrAuCl/AgOTs,IPrAuCl/AgTFA, IPrAuOTf, PEPPSI-IPr/AgOTf, PdCl₂(PPh₃)₂/AgOTf,PPh₃AuTFA, PPh₃AuCl/NaTFA, or CuCN*2LiCl, as well Na salts of each ofthese where Ag is replaced with Na.

In general, reaction schemes (1)-(123) to produce the organoboroncompounds of the present disclosure can be formed using the followinggeneral guidelines. The following general reaction parameters can beused to perform reaction schemes (1)-(123) to form the products of thepresent disclosure. In an exemplary embodiment, the reactant(s) (e.g.,such as those in schemes (1) to (123)) can be first reacted with a base,such as NaH, KH, CaH₂, sodium dimsyl, sodium pentadieneide, diethylzinc, or n-butyllithium or a transmetallation partner such as iPrMgCl inan appropriate solvent, such as toluene, benzene, hexane,dichloroethane, dichloromethane, tetrahydrofuran, cyclopentyl methylether, tert-butyl methyl ether, diethyl ether, or triethylamine at atemperature in the range of about −78° C. to 50° C. for less than 1minute to about 30 minutes.

Next, the mixture can be reacted with a salt of BX² _((1 or 2)) at aboutroom temperature for about 10 to 60 minutes. Then the mixture can be,optionally, reacted with a Lewis acid metal catalyst or stoichiometricreagent at a temperature of about 25° C. to 110° C. for about 1 to 24hours. In some instances, a promoter, such as the sodium, potassium,lithium, and silver salts of trifluoroacetic acid, p-toluenesulfonicacid, triflic acid, bis(trifluoromethane)sulfonimide,hexafluoroantimonic acid, hexafluorophosphoric acid, or tetrafluoroboricacid, may also be used. Alternatively to using a catalyst, the mixturecan be heated to a temperature of about 75 to 130° C. to initiate thereaction for about 15 to 48 hours.

Optionally, for some substrates the mixture can be reacted with acompound of BX² _((1 or 2)) at about 25° C. to 110° C. for about 1 to 24hours in the presence of a Lewis acid metal catalyst or stoichiometricreagent. In an embodiment, the substrates could be selected from theabove lists containing esters (COOR like COOCH₃ or thioethers SR, SCH₃).In some instances, a promoter, such as the sodium, potassium, lithium,and silver salts of trifluoroacetic acid, p-toluenesulfonic acid,triflic acid, bis(trifluoromethane)sulfonimide, hexafluoroantimonicacid, hexafluorophosphoric acid, or tetrafluoroboric acid, may also beused. Alternatively to using a catalyst, the mixture can be heated to atemperature of about 50 to 130° C. to initiate the reaction for about 15to 540 hours.

Optionally, the cyclic organoboron compound (e.g., such as those with(B′)) can be reacted with a diol, such as pinacol, or with acidic orbasic or neutral water, or with a diacid such as N-methyliminodiaceticacid, or with an ionic salt, such as potassium bifluoride, and an aminesuch as trimethylamine in an appropriate solvent, such as toluene,benzene, dichloroethane, dichloromethane, tetrahydrofuran, cyclopentylmethyl ether, diethyl ether, trimethylamine, or triethylamine at atemperature of about 25° C. to 110° C. for 30 to 180 minutes to form afinal cyclic organoboron compound.

The order of the steps and the order of the addition of additives,promoters, catalysts, and stoichiometric reagents can be adjusted orchanged so long as the products are still produced. In an embodiment,the conversion can be greater than about 90% or greater than about 95%.

In an embodiment, the amount of Lewis acid metal catalyst used can beabout 1 mol % to about 25 mol % or about 2.5 mol % to about 10 mol %.The amount of a stoichiometric Lewis acid metal reagent can be about 30mol % to about 100 mol %. The concentrations of the components can beadjusted accordingly depending upon the reactants, products,temperature, pH, reaction time, and the like. Examples 1-4 and schemes(1)-(123) illustrates an exemplary method and compounds formed using anembodiment of the method.

FIGS. 1.1A-1.1H and 6.1-6.13 illustrate embodiments of variousorganoboron compounds that can be made using reaction schemes (1)-(123).X, X¹, X², X³, Y, [B], (B′), R, R¹, R², R³, R⁴, R⁵ R⁶, R⁷, and R⁸ aswell as n, y, p, and q are defined above. Now having described thereactions and products in general, additional detail will be describedbelow.

Schemes (1) to (3) illustrate the formation of the organoboron productswhere the starting compound includes C═O, C═N, or C═S and the C—Cmultiple bond is an alkyne.

Schemes (4) to (6) illustrate the formation of the organoboron productswhere the starting compound includes an alcohol, amine, or a thiol andthe C—C multiple bond is an alkyne.

Schemes (7) to (9) illustrate the formation of the organoboron productswhere the starting compound includes C═O, C═N, or C═S and the C—Cmultiple bond is an alkene.

Schemes (10) to (12) illustrate the formation of the organoboronproducts where the starting compound includes an alcohol, amine, or athiol and the C—C multiple bond is an alkene.

Schemes (13) to (15) illustrate the formation of the organoboronproducts where the starting compound includes C═O, C═N, or C═S and theC—C multiple bond is an allene.

Schemes (16) to (18) illustrate the formation of the organoboronproducts where the starting compound includes an alcohol, amine, or athiol and the C—C multiple bond is an allene.

Schemes (19) to (22) illustrate the formation of the organoboronproducts through an intermolecular reaction where the starting compoundincludes an alcohol, amine, or a thiol and the C—C multiple bond is analkyne, alkene, or allene.

Schemes (23) to (25) illustrate the formation of the organoboronproducts through an intermolecular reaction where the starting compoundincludes X⁴ (a halide or pseudohalide), X³ (any non-hydrogen atom), andthe C—C multiple bond is an alkyne or alkene.

Schemes (26) to (37) illustrate the formation of the organoboronproducts through an oxyboration reaction. R¹, R², R³, R⁴, [B], Y, and nare defined above. The reaction can be initiated using a catalyst, suchas those described herein or temperature (e.g., about 110 to 130° C.)without the use of a catalyst.

The following reaction provides mechanistic illustration of the reactionthat may occur in schemes (26) to (37).

Activated Substrates: With and without Catalysts

Illustrative examples products that can be produced using schemes (26)to (37) include:

Schemes (38) to (41) illustrate the formation of the organoboronproducts through an oxy/thioboration reaction across alkynes. R¹, R²,R³, R⁶, R⁷, R⁸, [B], X, Y, p, and n are defined above. The reaction canbe initiated using a catalyst, such as those described herein ortemperature (e.g., about 110 to 130° C.) without the use of a catalyst.

The following reaction provides an illustration of the reaction that mayoccur in schemes (38) to (41) as well as products.

Schemes (42) to (45) illustrate the formation of the organoboronproducts through an oxy/thioboration reaction across alkenes. R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, [B], X, Y, p, and n are defined above. Thereaction can be initiated using a catalyst, such as those describedherein or temperature (e.g., about 110 to 130° C.) without the use of acatalyst.

Schemes (46) to (49) illustrate the formation of the organoboronproducts through an oxy/thioboration reaction across allenes. R¹, R²,R³, R⁴, R⁵, R⁶, R⁷, R⁸, [B], X, Y, p, and n are defined above. Thereaction can be initiated using a catalyst, such as those describedherein or temperature (e.g., about 110 to 130° C.) without the use of acatalyst.

The following reaction provides an illustration of the reaction that mayoccur in schemes (46) to (49) as well as products.

Schemes (50) to (53) illustrate the formation of the organoboronproducts through formal borylation across alkynes. R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, [B], X, Y, p, and n are defined above.

The reaction can be initiated using a catalyst, such as those describedherein or temperature (e.g., about 45° C. to 130° C.) without the use ofa catalyst.

The following reaction provides an illustration of the reaction that mayoccur in schemes (50) to (53) as well as products.

Scheme (54) illustrates the formation of the organoboron productsthrough intermolecular carboboration via boron enolates. R¹, R², R³, R⁴,R⁵, and [B]—X are defined above. The reaction can be initiated using acatalyst, such as those described herein or temperature (e.g., about 110to 130° C.) without the use of a catalyst.

The following reaction provides an illustration of the reaction that mayoccur in scheme (54) as well as products.

Schemes (55) to (78) illustrate the formation of the organoboronproducts through intermolecular carboboration via boron enolates. R¹,R², R³, R⁴, R⁵, and [B]—X are defined above. The reaction can beinitiated using a catalyst, such as those described herein ortemperature (e.g., about 110 to 130° C.) without the use of a catalyst.

The following reactions provide an illustration of the reaction that mayoccur in schemes (55) to (78) as well as products.

Scheme (79) illustrates the formation of the organoboron productsthrough a tandem allylboration/oxyboration reaction. R¹, R², R³, (B′),and [B] are defined above. The reaction can be initiated using acatalyst, such as those described herein or temperature (e.g., about 110to 130° C.) without the use of a catalyst.

The following reactions provide an illustration of products that mayresult for a reaction as shown in scheme (79).

Schemes (80) to (103) illustrate the formation of the organoboronproducts through an aminoboration reaction. R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, [B], X1, X2, q, and n are defined above. The reaction can beinitiated using a catalyst, such as those described herein ortemperature (e.g., about 110 to 130° C.) without the use of a catalyst.

The following reactions provide an illustration of products that mayresult for a reaction according to schemes (80) to (103) as well asproducts.

Schemes (104) to (123) illustrate the formation of the organoboronproducts through amidoboration/thioamidoboration/amidinoborationreactions. R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, [B], X1, X2, q, and n aredefined above. The reaction can be initiated using a catalyst, such asthose described herein or temperature (e.g., about 110 to 130° C.)without the use of a catalyst.

The following reactions provide an illustration of reactions andproducts that may result for a reaction according to schemes (104) to(123) as well as products.

R¹ and R² can be H or alkyl

Borylated Pyridone and Isoquinolinone Examples (X¹=O, X²=N, X³=None,n=0)

EXAMPLES

Now having described the embodiments of the disclosure, in general, theexamples describe some additional embodiments. While embodiments of thepresent disclosure are described in connection with the example and thecorresponding text and figures, there is no intent to limit embodimentsof the disclosure to these descriptions. On the contrary, the intent isto cover all alternatives, modifications, and equivalents includedwithin the spirit and scope of embodiments of the present disclosure.

Example 1

A method for the intramolecular anti addition of boron-oxygen bondsacross alkynes is disclosed. This alkoxyboration reaction is conductedas a one-pot sequence starting from 2-alkynylphenols and generates3-benzofuranyl boronic esters inaccessible using other borylationmethods. The products are isolated as the corresponding trifluoroboratesalts or MIDA boronate for synthetic ease.

Discussion:

We have developed an alkoxyboration reaction of alkynes tosimultaneously install new C—O and C—B bonds from the easily generatedB—O bonds of boric esters (such as A).

This new reactivity is compatible with a wide variety of functionalgroups sensitive to other borylation methods and provides access to newbench-stable organotrifluoroborate or MIDA boronate coupling partners.

We envisioned that an intramolecular anti-alkoxyboration reaction couldbe promoted by a Lewis acidic metal catalyst. A variety of metalcatalysts were examined for competence in converting boric ester A intoboronic ester B (Table 1, Example 1). In the absence of catalyst, noconversion of boric ester n was observed (entry 1). The N-heterocycliccarbene gold complexes IPrAuOH and IPrAuCl (entries 2 and 3) gaveunreacted boric ester A. However, IPrAuCl with a variety of silver saltactivators afforded the desired alkoxyboration catalyst in highconversion (entries 4-6). Identical reactivity was observed withauthentic IPrAuOTf, eliminating the possibility of a “silver effect”(entry 7). Interestingly, other commonly used late transition metalcomplexes were found to be ineffective as alkoxyboration catalysts(entries 8-10).

Table 1, Example 1. Optimization of alkoxyboration metal catalyst.

Conversion^(b) Entry Catalyst (B:A) 1 None only A 2 IPrAuOH only A 3IPrAuCl only A 4 IPrAuCl/AgOTf >95:5 5 IPrAuCl/AgOTs >95:5 6IPrAuCl/AgTFA >95:5 7 IPrAuOTf >95:5 8 PEPPSI—IPr/AgOTf^(c,d) only A 9PdCl₂(PPh₃)₂/AgOTf^(c,d) only A 10 IPrCuCl/AgTFA only A IPr =1,3-bis(2,6-diisopropylphenyl)-1,3-dihydro-2H-imidazol-2-ylidene^(a)Conditions: 0.10 M A in 1,2-dichloroethane. ^(b)Determined by ¹H and¹¹B NMR spectroscopy. ^(c)Using 20. mol % AgOTf. ^(d)Reaction time, 6 h.

Further optimization of the reaction conditions resulted in a one-potprocedure starting from 2-alkynyl phenols (Scheme 1A, Example 1 as shownin FIG. 1.3). Following deprotonation of substrate C by NaH, the boricester moiety was installed by electrophilic trapping usingB-chlorocatecholborane, a commercially available reagent used in thedeprotection of MOM-protected alcohols. Heating intermediate A in thepresence of catalytic IPrAuCl/NaTFA afforded the desired alkoxyborationproduct B in high conversion. In this one-pot procedure, NaTFA was usedas an activator instead of the silver salts shown in Table 1 due to itstolerance of the equivalent of NaCl present after installation of theboric ester in step 2.

Isolation of alkoxyboration product B proved to be challenging. Theelectron-rich nature of the 3-benzofuranyl system renders the C—B bondsensitive to protonolysis by atmospheric moisture. We therefore soughtto isolate alkoxyboration product B as the corresponding MIDA boronateor trifluoroborate salt, both of which are air-stable indefinitely.

Treatment of a microscale alkoxyboration reaction mixture withN-methyliminodiacetic acid (H₂MIDA) allowed for isolation of the desiredproduct in 46% yield (Scheme 1B, Example 1 as shown in FIG. 1.4) withthe protodeboronated product as the mass balance. Alternatively,treatment of the alkoxyboration reaction mixture with KHF₂ afforded thebenzofuranyl trifluoroborate salt in 47% yield. For synthetic ease andoptimal yields, we therefore opted to isolate the catechol boronic esteralkoxyboration products as the corresponding triflouroborate salts.

With optimized reaction and isolation conditions in hand, we set out toexplore the substrate scope of this alkoxyboration reaction (FIG. 1.5).

Simple aryl and alkyl substitution at the benzofuran 2-position istolerated with high yield (a). The reaction is regioselective when usinga diethynylphenol to afford alkyne-substituted benzofuran (b). Unliketraditional metalation/electrophilic trapping methods of generatingboronic esters, the alkoxyboration reaction is compatible with a varietyof reactive functional groups, such as aryl halides (c, j), silyl ethers(d), free alcohols (e, n), amides (m, n), esters (f, g, i, k, and l),nitriles (j), protected amino acids (o), and aldehydes (h), and isexpected to be compatible with ketones (l). The high degree offunctionality available in the alkoxyboration products provides manyfunctional group handles for subsequent transformations.

Example 2

Despite nearly 70 years of research into the addition of B—X σ bonds toC—C multiple bonds, a method for B—O bond activation has not yet beenreported. Such a transformation could allow for the synthesis ofversatile oxygen-containing organoboron reagents for organic synthesis.We herein report the realization of an alkoxyboration reaction, addingB—O σ bonds to alkynes. O-Heterocyclic boronic acid derivatives can beproduced using this transformation, which is mild and exhibits broadfunctional group compatibility.

Discussion:

Boronic acids and their derivatives are versatile reagents in modernorganic synthesis, and the hydroboration reaction is a well-establishedmethod for generating these building blocks through the addition of B—Hbonds across C—C multiple bonds (1). First described by Hurd in 1948 (2)and later developed in detail by Brown (3), this reaction has inspiredmany catalyzed variants (4, 5). Recently, several compelling examples ofrelated B—X bond addition reactivity have been reported for X═C (6, 7),Si (8, 9), Sn (10), and S (11) (FIG. 2.1A). These transformationsgenerally proceed through the oxidative addition of a catalytictransition metal such Ni(0), Pd(0), or Pt(0) into the B—X σ bond.

Despite this progress, the corresponding activation of B—O bonds andaddition to C—C multiple bonds—alkyoxyboration—has remained elusive for65 years (12,13). This striking dearth of B—O bond activation reactivitymay be due to the high strength of the B—O bond (14), rendering itunreactive towards oxidative addition and thus preventing the successfulapplication of Ni, Pd, or Pt catalysis (6-11). Given that ethers arefound in many diverse classes of natural products (15) and in nearly 25%of the top-grossing pharmaceuticals in the United States for 2012 (16),the development of an alkoxyboration reaction could allow for thepreparation of oxygen-containing building blocks useful in drugdiscovery and materials science (16,17).

Herein we report the realization of an alkoxyboration reaction ofalkynes, through which new O-heterocyclic organoboronate couplingpartners are available for downstream functionalization. The highfunctional-group tolerance of this reaction enables downstream divergentsynthesis of functionalized benzofurans—the ability to accesses multiplebenzofurans from one bench stable precursor. In contrast, currentmethods for synthesizing benzofurans often rely on harsh conditions thatlimit compatibility with functional groups desirable for divergentsynthesis (18).

We envisioned that the desired alkoxyboration reactivity could bepromoted through an activation pathway employing a bifunctional Lewisacidic/Lewis basic catalyst, which could simultaneously activate boththe alkyne and the B—O σ bond partners. We anticipated that this uniquestrategy could allow for the anti addition of B—O bonds across alkynesby circumventing the previous problematic strategy of oxidative cleavageof the B—O bond.

Our optimized one-pot procedure begins with 2-alkynyl phenols (1), whichare converted into the requisite boric ester intermediate 2 using thereadily available reagent B-chlorocatecholborane (Scheme 2A, Example 2,FIG. 1.5). Treatment of this intermediate with the commerciallyavailable Lewis acidic gold(I) precatalyst IPrAuCl and NaTFA affordsalkoxyboration product 3 in good to excellent conversion. Interestingly,our examination of alternative n-Lewis acidic transition metal catalystsrevealed no other active catalysts aside from Au(I) (19). For syntheticease, the catechol boronic ester alkoxyboration product 3 was convertedinto either the organotrifluoroborate (20) or N-methyliminodiacetic acid(MIDA) boronate (21) derivative, 4, both of which are air stableindefinitely.

Organotrifluoroborate 4a is readily isolated in high yield using achromatography-free purification, making this derivatization methodparticularly amenable to applying the alkoxyboration reaction onpreparative scale (FIG. 2.2). The corresponding MIDA derivative (4b)provides an option for purification by silica gel chromatography, butthis comes at the cost of slightly diminished yield. Single-crystalX-ray diffraction analysis of 4b allowed for the unambiguousidentification of the alkoxyboration product.

The alkoxyboration reaction is tolerant of a variety of functionalgroups suitable for downstream reactivity. Aryl bromide 4c,silyl-protected alcohol 4d, terminal alkyne 4f, amide 4g, esters 4h and4i, and the functionally-dense iodonitrile 4j are compatible with thereaction conditions. Many of these alkoxyboration reactions proceedsmoothly at 50° C., although the reactions generating 4d, 4g, 4h, and 4jrequired heating to 90° C. in order to affect full conversion. Weattribute the relatively slow formation of 4d to the high stericencumbrance from the silyl ether at the 2-position of the benzofuran.The cyclization of substrates containing Lewis basic nitrogen atoms(forming 4g, 4h, and 4j) was likely retarded by reversible N—Bcoordination that was observed by ¹¹B nuclear magnetic resonance (NMR)spectroscopy.

Notably, many of these products contain functional groups incompatiblewith commonly employed methods of benzofuran synthesis (18), includingvia other borylation techniques (FIG. 2.3). In one frequently usedborylation technique, an aryl lithium intermediate is trapped by a boronelectrophile (Method 1); thus electrophiles such as carbonyl or nitrilegroups and enolizable protons are not generally tolerated due to thehighly nucleophilic and basic nature of the requisite organolithiumintermediate (22). Aryl halides may also suffer from undesiredlithium/halogen exchange. The Miyaura borylation is a more mildalternative that is compatible with electrophilic functional groups(Method 2), but aryl halides are not tolerated because this reaction iscatalyzed by Pd(0), which also activates aryl halide bonds (23).Finally, the Ir-catalyzed C—H activation/borylation reaction is aneffective means of accessing aryl boronic acid derivatives through C—Hactivation (Method 3), but this reaction is regioselective for either 2-or 7-borylation; 3-borylated benzofurans such as those available throughthe alkoxyboration reaction cannot be synthesized regioselectivelythrough C—H activation/borylation (24).

We set out to demonstrate the utility in divergent synthesis of thealkoxyboration products enabled through this synthesis in subsequentfunctionalization steps. Rh-catalyzed conjugate addition of 4a intomethyl vinyl ketone using the method developed by Batey (25) providesβ-benzofuranyl ketone 6 in moderate yield (eq 1). Organotrifluoroborate4i was subjected to Suzuki-Miyaura coupling conditions described byMolander and Biolatto (26) to afford the cross-coupled product3-arylated benzofuran 8 with concomitant methanolysis of the ethyl ester(eq 2). These two transformations suggest the potential for broadapplicability of these functionalized alkoxyboration products in avariety of C—C bond-forming reactions.

We next explored the scalability of the alkoxyboration reaction andtolerance of lower catalyst loading. Bromide-containing phenol 1c wassuccessfully converted to more than 1 g of MIDA boronate 4c on a 5.1mmol scale with 2.0% gold catalyst (eq 3). Full conversion of startingmaterial was affected even with a lower Au catalyst loading. Thisconvenient scalability demonstrates that quantities of O-heterocyclicboronic acid derivatives sufficient for multistep synthesis may beprepared using the alkoxyboration method.

Having demonstrated the utility of this transformation in generatingmembers of the benzofuran class of O-heteroaryl boronic acidderivatives, we explored its application to the synthesis of anon-aromatic oxygen-containing heterocycle (eq 4). Simple andcommercially available homopropargyl alcohol 9 was subjected to standardalkoxyboration reaction conditions to prepare the dihydrofuran product10. This substrate demonstrates the potential for great generality inthe alkoxyboration reaction: The reaction features low labor “setupcost” by employing simple starting materials to generate highlyvalue-added O-heterocyclic organoboronate compounds in one syntheticstep, and the cyclization proceeds without requiring the gain of productaromaticity or the need for a fused ring system that enforces aconformational bias towards cyclization.

In accordance with our strategy for bifunctional Lewis acidic/Lewisbasic substrate activation, we propose the catalytic cycle shown inScheme 2B, Example 2. The bifunctional catalyst IPrAuTFA can begenerated in situ from IPrAuCl and NaTFA. Reaction of the Lewis basictrifluoroacetate moiety with electrophilic boric ester 2a givesnucleophilic boronate 12.

The resulting Lewis acidic Au(I) cation may then bind to the alkyne(13), increasing its electrophilicity. Nucleophilic attack on thealkyne-Au π complex by the phenol B—O bond would provide neutralintermediates: boron electrophile 14 and organogold nucleophile 15,which could recombine to regenerate 11 with concomitant formation of theobserved alkoxyboration product 3a. Thus, the IPrAu⁺ moiety of thecatalyst activates the alkyne for nucleophilic attack, and the TFAcounterion allows for reversible tuning at boron from electrophilic tonucleophilic. This reaction manifold is fundamentally unique from themetal-catalyzed addition of B—C, B—Si, B—Sn, and B—S addition reactions,which often proceed through oxidative addition of a low-valent metalcatalyst into the B—X bond. We believe that the new activation strategyemployed in the alkoxyboration reaction could be extended to other typesof B—X bonds in order to provide additional reactivity complementary topreexisting methods.

This alkoxyboration reaction proceeds through an unprecedented B—O bondactivation. This fundamentally new activation is showcased in a mild,scalable technique for the preparation of O-heterocyclic boronic acidderivatives and downstream functionalized benzofurans. The reactionprovides a simple new bond disconnection for constructing these motifswith different regioselectivity and broader functional groupcompatibility than existing methods. This compatibility yields highlyfunctionalized bench-stable cross-coupling and Michael addition partnersfor divergent synthesis that are not directly accessible usingalternative methods.

REFERENCES

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Example 3

FIG. 3.1 illustrates an embodiment of forming a boronic compound. Thearyl bromide starting material is converted to the correspondingGrignard reagent through a magnesium/halogen exchange reaction.Treatment with a stoichiometric copper reagent, such as CuCN.2LiCl,promotes anti addition across the tethered alkyne to form a 2-metallatedindole. Trapping of this organocopper nucleophile with an electrophilicboron reagent or other boron transmetalation reagent such asB-chlorocatecholborane, B-chloropinacolborane, orB-trifluoroacetocatecholborane is expected to provide the 2-borylatedindole shown (product shown for trapping with B-chlorocatecholborane),which could be converted to the corresponding organotrifluoroborate orMIDA boronate derivative.

Thus, this method provides selective borylation at the 2 position of thenew heterocyclic ring in a manner complementary to the 3-selectiveborylations shown in FIGS. 1.1A-2.3.

Example 4

In this Example an oxyboration reaction with activated substrates thatemploys B—O σ bond additions to C—C π bonds to form borylatedisoxazoles, which are potential building blocks for drug discovery.While this reaction can be effectively catalyzed by gold, it is thefirst example of uncatalyzed oxyboration of C—C π bonds by B—O σbonds—and only the second example that is catalyzed. This oxyborationreaction is tolerant of groups incompatible with alternativelithiation/borylation and palladium-catalyzed C—H activation/borylationtechnologies for the synthesis of borylated isoxazoles. Mechanisticexperiments, including a stoichiometric organogold-to-borontransmetalation reaction, identify a two-step transmetalation processwith breakdown of a tetracoordinate borate/cationic gold ion pair as therate-determining step in this transmetalation reaction and plausibly inthe overall catalytic oxyboration reaction. The complimentary bonddisconnections and functional-group tolerance enabled by this method arehighlighted in the synthesis of valdecoxib, a COX-2 inhibitor, and itsester-containing analog. The scalability of the reaction is demonstratedby a gram-scale uncatalyzed oxyboration reaction.

Isoxazoles¹ exhibit a wide variety of biological activities, includinganalgesic,² antibiotic,³ antidepressants,⁴ and anticancer⁵ activities.Consequently, borylated isoxazoles are valuable bench-stable buildingblocks for drug discovery.⁶⁻⁹ Oxyboration reactions that proceed throughthe addition of B—O σ bonds to C—C π bonds would be an attractive routeto these and other building blocks by transforming easily formed B—O σbonds into more difficult to form B—C σ bonds. Yet the addition of B—O σbonds to C—C multiple bonds had remained elusive for 65 years^(10,11)until our first report last year.^(12,13) We herein develop catalyzedand uncatalyzed oxyboration routes to borylated isoxazoles. This is thefirst report of uncatalyzed oxyboration of C—C π bonds with B—O σ bonds.The functional group tolerance of these methods provides access toborylated building blocks containing carbonyl, heterocyclic, and arylbromide functional groups that are incompatible with alternativemetalation routes for their production, and this oxyboration methodproduces exclusively the 4-borylated regioisomer. These examplesestablish the generality of oxyboration strategies^(12,13) to generateborylated heterocycles for drug discovery.

Specifically, compounds of this type may currently be accessed throughthe [3+2] cycloaddition reaction of nitrile oxides and alkynylboronatesas shown in Scheme 1. However, this method can produce two regioisomersand the alkynylboronate synthesis involves a lithiation step.¹⁴Alternatively, the Pd(0)-catalyzed Miyaura borylation¹⁵ andlithiation/electrophilic borylation¹⁶ have been used for the synthesisof borylated heterocycles, but, as with lithiation/cycloaddition, arylbromides and electrophilic functional groups are reactive under theseconditions.

Inspired by previous reports from Perumal¹⁷ and Che and Wong,¹⁸ whodemonstrated analogous Au-catalyzed rearrangements of oximes to form4-protonated isoxazoles without boron (i.e., cyclizing substrates 1 withno boron rather than borylated substrates 2), we considered thatanalogous routes to borylated

isoxazoles may be assessable through oxyboration. We hypothesized thatthis gold-catalyzed oxyboration reaction could proceed throughcarbophilic Lewis acid activation of the C—C π bond, a mechanisticallydistinct route to B-Element addition reactions.^(12,13) The oxyborationreaction developed here is an operationally simple one-pot procedurefrom oximes and requires no isolation of reaction intermediates (Scheme1).

Alkynyloximes (1) were prepared for oxyboration via O-borylation withcommercially available catecholborane (catBH) with concomitant evolutionof H₂, producing boric ester intermediates 2. Without isolation,treatment of these synthetic intermediates in the same pot withcatalytic IPrAuTFA initiated oxyboration to afford 4-borylatedisoxazoles 3 in good to excellent ¹H NMR yields (Table 1). These boronicesters were converted to pinacol (pin) boronic esters 4, which areisolable by silica gel chromatography and are bench-stable buildingblocks for a variety of downstream reactions.^(6,19)

The reaction was developed through initial studies with substrate 1a.Conversion of 1a to boric ester intermediate 2a and subsequent treatmentwith 2.5 mol % IPrAuTFA for 6 h at 50° C. afforded oxyboration product3a in 90% ¹H NMR spectroscopy yield, calculated from an externalmesitylene standard. A control reaction under identical conditions (6 h,50° C.) in the absence of catalyst yielded 3a in <1% ¹H NMR spectroscopyyield. Interestingly, oxyboration of 1a could be carried out undercatalyst-free conditions, albeit with higher temperatures and longerreaction times. Specifically, heating 1a to 110° C. for 17 h afforded 3ain 58% ¹H NMR spectroscopy yield, with the remaining of the mass balanceaccounted for by competing formation of the 4-H (unsubstituted)isoxazole. Similarly, cyclization of 1c under catalyst-free conditionsof 110° C. for 17 h produced 3c in 89% ¹H NMR yield. We hypothesize thatthe Michael-acceptor/polar character of the starting materials enablesthis catalyst-free oxyboration through lowering the barrier ofcyclization (eq 1); alternatively, the nucleophilic nitrogen lone pair²⁰of the hydroxylimine may coordinate and activate the boronIdentification of this class of activated substrates thus providesaccess to catalyst-free reactivity that was not possible previouslywithin our earlier reported oxyboration substrates.¹²

TABLE 1 Example 4. Initial Reaction Development With and WithoutCatalyst. IPrAuTFA Uncat. Uncat. R¹/R² 6 h, 50° C. 6 h, 50° C. 17 h,110° C. 1a Ph/Bu 90% <1% 58% 1c 4-BrPh/Bu 93% 4% 89% 1f Ph/TMS 87% <1%<1%

In contrast to the reactivity exhibited by 1a and 1f, when silylated 1fwas used as the substrate for catalyst-free oxyboration, only B—O σ bondformation was observed (boric ester 2f), and no cyclized products wereformed even after an extended time of heating at 110° C.

This lack of reactivity possibly derives from the steric hinderance andthe electron-donating ability of the trimethylsilyl group²¹ adjacent tothe alkyne carbon, which may alter the polarization of the alkyne,rendering it less susceptible toward nucleophilic attack in the keycarbon-oxygen bond-forming/cyclization step (proposed mechanism, Scheme1). Due to its reduced temperatures, shorter reaction times, and actionwith the silylated substrate, the metal-catalyzed route was selected forfurther optimization and isolation.

This oxyboration method provided a new set of bond disconnections toaccess previously unreported isoxazole pinacol boronic esters 4a-4k(except 4f¹⁴) as shown in Table 1. The numbers in parentheses denote the¹H NMR spectroscopy yield of catechol boronic ester 3 relative to anexternal standard. The numbers outside the parentheses on the first rowdenote the isolated yield of bench-stable pinacol boronic ester 4.²² Thenumbers outside the parentheses on the second row correspond to thereaction time of the uncatalyzed oxyboration when run at 110° C. Aftercompletion of the catalytic reaction, PPh₃ was employed to quench theactive catalyst IPrAuTFA by trapping it as the catalytically inactive[IPrAuPPh₃]⁺.²³ A control reaction with catalytic NaTFA in place ofIPrAuTFA exhibited no conversion of starting material 2a to productafter 6 h at 50° C., confirming a key role for the carbophilic Lewisacid.

We herein compare the catalyzed reaction yields with those obtainedthrough the uncatalyzed method for each substrate. With the exception ofsilylated 1f, all substrates showed uncatalyzed reactivity at longerreaction times, which ranged typically from 20 h to 65 h. Bulkysubstituents such as t-butyl and trimethylsilyl, however, only producedvery low ¹H NMR spectroscopy yield (24% for 3d and <1% for 3f), with thestarting materials remaining. Thus they required catalysis forsynthetically useful product formation. The electron poor p-CF₃substrate and furyl substrate, required a rather lengthy 18-21 d toreach full conversion at 110° C. In many cases, the cost benefit ofobtaining the product under catalyst-free conditions may be desired inexchange for elevated temperatures and marginally longer reaction times,most notably with 4c, 4e, 4h, 4i, 4k, reactions which achieved similar¹H NMR yields to the catalyzed reactions in 20-65 h.

Interestingly, substrates that exhibited slow conversions under thecatalyzed conditions for apparent electronic reasons (rather than stericreasons) such as 1i and 1k were the faster converting substrates underthe uncatalyzed conditions; it may be that the electronics that favor πLewis acid catalysis though gold-alkyne binding disfavor cyclization inthe absence of a catalyst. This orthogonality in electronic and stericsubstrate reactivity highlights the complementarity provided by thecatalyzed and uncatalyzed methods.

Both the metal-catalyzed oxyboration reaction and the uncatalyzedoxyboration reaction are tolerant of functional groups that would besensitive to alternative methods for the borylation of heterocycles. Forexample, aryl bromide 1c smoothly undergoes oxyboration to produceborylated isoxazole 3c (93% ¹H NMR yield, 65% isolated yield of 4c witha catalyst; 91% ¹H NMR yield without a catalyst). This substrate wouldbe sensitive to a lithiation/borylation sequence^(16,24) due tocompetitive lithium/halogen exchange,²⁵ and to an alternativepalladium-catalyzed borylation¹⁵ due to competitive oxidative additionof the aryl-bromide bond. The nitro group in 1e and the ester group in1k are similarly tolerated, producing oxyboration product 3e in 90% ¹HNMR yield (60% isolated yield of 4e) and 3k in 94% ¹H NMR yield (64%isolated yield of 4k) under catalysis, whereas these groups areintolerant of alternative lithiation techniques.¹⁶ Furan-substituted 4bdemonstrates the complementary bond disconnections enabled byoxyboration to avoid competitive ortho-borylation of the furan ring²⁶which would compete under alternative lithiation/borylation strategies(85% ¹H NMR yield of 3b; 71% isolated yield of 4b).

In addition, heteroaryl (4b), aliphatic group (4d), electron-poor aryl(4e, 4j and 4k), silyl (4f), and electron-rich aryl (4g and 4i) were allcompatible with the reaction conditions. Some substrates required higherreaction temperature and/or longer reaction time to achieve fullconversion under catalytic conditions, while no reaction was observedwhen the same conditions were applied in the absence of an Au catalyst.Oxyboration products 3d and 3f required 110° C. for 4 h and 90° C. for24 h, respectively, which may be caused by the steric hinderance of thet-butyl and the silyl groups. Electron-rich aryl 3i and heteroaryl 3brequired heating at 60° C. for 24 h and 50° C. for 24 h, respectively,which may be attributed to the electron-donating ability of thesesubstituents to reduce the electrophilicity of boron.

A plausible catalytic cycle for the π Lewis acid catalyzed oxyborationreaction is shown in Scheme 2A that highlights the proposed activationof the C—C π bond by the carbophilic Lewis Table 2, Example 4. ReactionSubstrate Scope. Substrates Shown in Blue Are Incompatible withAlternative Routes. All Substrates Give Exclusively 4-BorylatedRegioisomer.

Acid catalyst^(27,28) that provides a mechanistically distinct route forB—X σ bond addition, and possible concurrent activation of the B—O σbond by coordination of trifluoroacetate ion in intermediate 6.Subsequent addition of the nucleophilic B—O σ bond to the resultingAu-alkyne π complex of intermediate 6 in a concerted manner forms thecarbon-oxygen bond of the isoxazole core and generates a new carbon-gold6-bond as shown in intermediate 7.

Alternatively, the π Lewis acid catalyzed cyclization steps can occur ina different order, in which the nucleophilic oxygen of the boric ester 8attacks the activated alkyne to generate an oxonium ion 9 in the firststep, and then the outersphere trifluoroacetate ion removes the Bcatgroup in the second step to produce 7 and 10 (eq 1). This pathway issupported by similar mechanisms in gold-catalyzed and -mediatedcyclizations, such as has been detected by ¹H NMR spectroscopy instoichiometric studies,²⁹ proposed as intermediates in the fluorinationof oxime ethers to generate 4-fluoroisoxazoles,³⁰ and detected as likelycatalytic intermediates in gold and palladium cooperatively catalyzedcyclization/cross-coupling reactions.^(23,31)

In the next step of the proposed mechanism, the carbon-gold bond in 7 isnucleophilic at carbon^(13,32,33) and is primed for transmetalation withelectrophilic boron intermediate 10. The mechanism of the reactionbetween 7 and 10 to form ion pair 11 may involve an electrophilicaromatic substitution, with rearomatization and loss of the AuIPrcation. The accessibility of this transmetalation step is notwell-established; to our knowledge, our report last year is the first oftransmetalation from organogold to boron.^(12,13,34) The reversereaction from organoboron to gold is better studied,³⁵⁻³⁸ as is thegeneral ability of organogold compounds to transmetalate with othermetals and metalloids.^(31,39-43)

The proposed mechanism for the uncatalyzed oxyboration reaction is shownin Scheme 2B. A nucleophile (Nu) could coordinate to boron in 2,activating the B—O σ bond as shown in 13. This tetracoordinate boronspecies 13 then undergo cyclization with 14 to form boronate 3 andregenerate the nucleophile. The nature of the nucleophile is currentlyunknown but it may be another molecule of 2, potentially coordinating toboron through the nucleophilic lone pair on the nitrogen.²⁰

Mechanistic Studies.

Optimization of the counterion in the catalyst IPrAuX produced yielddata consistent with the assignment of an active role for the X⁻ ratherthan simply a spectator required for charge balance. Specifically, thecatalyst IPrAuOTs, with the less coordinating tosylate counterion isoften employed in other reported Au(I) catalyzed reactions,^(44,45) aresult attributed to its weakly coordinated tosylate and thus highlyLewis acidic Au⁺ cation equivalent. Yet in oxyboration, this tosylatecatalyst produced product 3a in lower yield than did IPrAuTFA, despitethe fact that trifluoroacetate anion is more strongly coordinating andshould therefore produce a weaker and less active gold catalyst^(44,45)(¹H NMR spectroscopy yield at t=6 h for IPrAuOTs (34%; IPrAuTFA 90%).This result is somewhat surprising in light of the other reportedapplications of weakly coordinating anions in homogeneous Au(I)catalysis;^(44,45) and is consistent with the hypothesis that the anioncould be assisting the reaction by coordinating to boron to activate theB—O σ bond in borate

and/or by assisting transmetalation in 10 or 11.¹² The catalyst IPrAuTFAproved an optimal balance of counterion coordinating ability. Thecomplex IPrAuOAc, with the more strongly coordinating acetate ion⁴⁵ didnot lead to any detectable product formation.

In order to probe the viability of the proposed intermolecularorganogold-to-boron transmetalation reaction in our system, the proposedneutral organogold intermediate 7a was generated by independentsynthesis³⁰ (Scheme 3). In our hands, an attempted in situ synthesis ofTFA-Bcat (proposed intermediate 10), adapted from the previouslyreported synthesis of TfO-Bcat,⁴⁶ yielded multiple products. Wetherefore examined the stoichiometric transmetalation reaction betweenorganogold 7a and readily available B-chlorocatecholborane 15 as asubstitute (Scheme 3, see FIG. 7.1). This reaction produced theanticipated transmetalation product, catechol boronic ester 3a, in 96%¹H NMR yield, supporting the plausibility of this intermolecularorganogold-to-boron transmetalation step in our proposed mechanism. Awhite precipitate formed gradually during this reaction, which waspresumably coproduct IPrAuCl 17, and which accounted for the initiallydetected substoichiometric integration (at t=10 min) and eventualdisappearance (at t=2 h) of the ¹H NMR spectroscopy signalscorresponding to 17 in solution.

Interestingly, ¹H NMR spectroscopic analysis of the reaction at t=10min, prior to completion, characterized the mechanism of thistransmetalation reaction as a two-step process wherein an initial fasttransfer of the organic group from gold to boron to make an ion pair isfollowed by rate-determining breakdown of the ion pair to generate thefinal neutral products. In Scheme 2, 1, 1′, 1″ are the same proton inthe starting material, intermediate, and final product respectively.Specifically, ¹H and ¹¹B NMR spectroscopy analysis indicated that theconsumption of both starting materials was complete at the first datapoint, t=10 min, to generate ion pair 16. The ratio of 17 to finalneutral organoboron product 3a at this time point was 1:1.5 (¹¹B NMRsignal at 17.6 ppm for 16 and 31.0 ppm for 3a). This ion pair thendecomposed to yield 3a in 96% final ¹H NMR spectroscopy yield relativeto external standard.

This two-step transmetalation reaction from organogold-to-boronestablishes catalytic relevance to the previous observation oftetracoordinate boronate species in mixtures of organogold and boroncompounds in model systems with simple substrates.¹³ HRMS analysis ofthe catalytic oxyboration reaction mixture prior to completion of thereaction at t=30 min identified two complexes consistent with themechanistic proposal in Scheme 1: neutral organogold complex 7c (m/z[M]⁺=864.2803) and a second mass m/z [M]⁻=510.0458. Due to the identicalm/z of anionic complexes 11c and 5c, the mass could correspond to eitherspecies or both. The detection of neutral organogold complex 7c,however, suggests the possibility of a catalyst resting state involvingthe equilibrium between ion pair 11 with 7 and 10 (favoring 11, as seenin the stoichiometric NMR studies, with small concentrations of 7 and10) followed by breakdown of 11 to yield 3 and regenerate catalyst 12;although its detection alone is not sufficient to establish thecatalytic relevance of 7c. These studies suggest that the rate of theoverall catalytic cycle may be similarly dictated by the breakdown ofthe tetracoordinate boronate intermediate in the transmetalationreaction, which may serve as the rate-determining step.

The detection of TFA-coordinated boron complexes by HRMS is furtherconsistent with an active role for the counterion in the oxyborationreaction rather than simply serving as a spectator to balance the chargeon gold(I), as previously suggested by the catalyst optimizationstudies.

In order to further probe the intermolecularity of the proposed reactionthrough the intermediacy of 7 and 10, a double-label crossoverexperiment was conducted. Specifically, 2.5 mol % IPrAuTFA was added to0.5 equiv of 2a and 0.5 equiv of 18 in a single reaction vessel (eq 2).Non-crossover products 3a plus 20 and crossover products 21 plus 3c wereobserved by ¹H and ¹¹B NMR spectroscopy. However, a control experimentrevealed that the starting boric esters 2a and 18 underwent rapid ligandredistribution at ambient temperature even in the absence of catalyst,forming all four possible boric ester starting materials (2a, 2c, 18,19). Exchange of the catechol groups in the starting materials wasobserved as line broadening in the ¹H NMR spectra of the mixturegenerated by combination of 2a and 18. This exchange on the ¹H NMRspectroscopy timescale at ambient temperature therefore wassignificantly more rapid than both the catalyzed and uncatalyzedoxyboration reactions and therefore precluded the employment of adouble-label crossover experiment in the evaluation of theintermolecularity of the oxyboration mechanism.

Synthetic Utility.

The utility of the oxyboration reaction to generate building blocks forpharmaceutical targets was showcased through the synthesis ofvaldecoxib, a non-steroidal anti-inflammatory drug (NSAID)⁴⁷ and itsanalog. Our synthetic route is shown in Scheme 4. Under standardcatalytic conditions, bench-stable pinacol boronate building blocks 23and 4k were generated from oximes 22 and 1k in 71% and 64% isolatedyields, respectively. Suzuki cross coupling of these borylatedisoxazoles with p-bromobenzene sulfonamide 24 afforded valdecoxib 25 andvaldecoxib ester analog 26 in 62% and 74% isolated yields, respectively.This synthesis provides the key substituted organoboron building block23 in higher isolated yield, compared to the competing methodology with[3+2] cycloaddition of nitrile oxides and alkylboronates, which formedthe same organoboron 23 in only 54% isolated yield in a route employedin a previously reported synthesis of valdecoxib.¹⁴

Additionally, the application of oxyboration to the synthesis ofester-containing valdecoxib analog 26 showcases the utility of thefunctional group tolerance of this oxyboration method. Previouslyreported syntheses of valdecoxib from academic^(14,16) and industrial⁴⁷laboratories involve lithiation steps that are not compatible with esterfunctional groups. These applications demonstrate the versatility andefficiency of the oxyboration reaction for the construction ofpharmaceutical targets.

Access to a cost-effective uncatalyzed version of the reaction isparticularly desirable on scale, wherein the cost of the catalyst maybecome a significant consideration that outweighs time considerations.The uncatalyzed oxyboration reaction scales well. Compound 1a wassuccessfully converted to 1.7 g of pinacol boronate 4a on an 8 mmolscale under catalyst free conditions (eq 3). This convenient scalabilitydemonstrates that quantities of these heterocyclic boronic acid buildingblocks that are sufficient for multistep downstream synthesis may beprepared by this oxyboration method.

In conclusion, we have developed a method for preparing 4-borylatedisoxazoles via oxyboration. This reaction proceeds with catalyticgold(I), or for many substrates without an added catalyst in the firstreported uncatalyzed oxyboration reaction of C—C multiple bonds with B—Oσ bonds. The reaction conditions are sufficiently mild to formfunctionalized borylated isoxazoles in good yields and in exclusivelyone regioisomer. The utility and functional group compatibility of thismethodology was highlighted in the synthesis of valdecoxib and avaldecoxib ester analog. Probable reaction intermediates detected bymass spectrometry and by a stoichiometric transmetalation experimentbetween the organogold intermediate and the boron electrophile, areconsistent with a catalyzed mechanism in which the carbophilic Lewisacid catalyst activates the C—C π bond towards B—O σ bond, a newstrategy in B-Element addition reactions.¹²

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Supporting Information for Example 4

I. General Methods

All reagents were used as received from commercial sources unlessotherwise noted. Tetrahydrofuran, acetonitrile and triethylamine weredried by passing through an alumina column under argon pressure on apush still solvent system. Toluene-d8 was dried over CaH2, degassedusing three freeze-pump-thaw cycles, and vacuum transferred before use.Dioxane was degassed by sparging with nitrogen gas for 1 h.Manipulations were performed in a glovebox under nitrogen atmosphereunless otherwise noted. Analytical thin layer chromatography (TLC) wasperformed using Merck F250 plates and visualized under UV irradiation at254 nm, or using a basic aqueous solution of potassium permanganate.Flash chromatography was conducted using a Teledyne Isco Combiflash® Rf200 Automatic Flash Chromatography System, and Teledyne Isco Redisep®35-70 μm silica gel. All proton and carbon nuclear magnetic resonance(1H and 13C NMR) spectra were recorded on a Bruker DRX-400 spectrometer,Bruker DRX-500 spectrometer outfitted with a cryoprobe, or a BrukerAVANCE-600 spectrometer. Boron nuclear magnetic resonance (11B NMR)spectra were recorded on a Bruker AVANCE-600 spectrometer. Fluorinenuclear magnetic resonance (19F NMR) spectra were recorded on a BrukerDRX-400 spectrometer. All coupling constants were measured in Hertz(Hz). Chemical shifts were reported in ppm and referenced to residualprotonated solvent peak (δH=7.26 ppm for CDCl3, δH=2.08 ppm ford8-toluene, δH=2.05 ppm for d6-acetone in 1H NMR spectroscopyexperiments; δC=77.16 ppm for CDCl3, δC=20.43 ppm for d8-toluene,δC=29.84 ppm for d6-acetone in 13C NMR spectroscopy experiments). 11Band 19F NMR spectroscopy experiments were referenced to the absolutefrequency of 0 ppm in the 1H dimension according to the Xi scale.High-resolution mass spectrometry data were obtained at the Universityof California, Irvine.

II. Synthetic Procedures

A. Preparation of Alkynyl Ketone SI-2(a-i). General Procedure.

Ketones were prepared according to a literature procedure. 1 Usingstandard Schlenk line, to a flame-dried round bottom flask equipped withstir bar under N2 atmosphere was added acid chloride SI-1 (10.0 mmol,1.00 equiv), PdCl2(PPh3)₂ (140 mg, 0.20 mmol, 2.0 mol %), CuI (76 mg,0.40 mmol, 4.0 mol %), Et3N (1.39 mL, 10.0 mmol, 1.00 equiv), and alkyne(1.0 equiv) in dry THF (50 mL) at 25° C. The resulting reaction mixturewas stirred at room temperature for 1 h. The reaction was quenched withDI water (30 mL). The aqueous layer was extracted with EtOAc (3×30 mL).The combined organic layers were washed with brine (30 mL), dried overMgSO4, filtered, and concentrated in vacuo. The resulting crude solidwas purified by silica gel flash column chromatography using an elutiongradient from 100% hexanes to 10% EtOAc in hexanes. Product-containingfractions were combined and concentrated in vacuo to afford SI-2.

1-phenylhept-2-yn-1-one (SI-2a) was obtained as yellow oil (1.60 g, 86%isolated yield). TLC (20% EtOAc/hexanes): Rf=0.50, visualized by UVabsorbance. 1H NMR (CDCl3, 500 MHz): δ 8.15-8.13 (m, 2H), 7.61-7.58 (m,1H), 7.49-7.46 (m, 2H), 2.51 (t, J=7.0 Hz, 2H), 1.67 (quintet, J=7.5 Hz,2H), 1.52 (sextet, J=7.5 Hz, 2H), 0.97 (t, J=7.5 Hz, 3H). This spectrumis in agreement with previously reported spectral data.²

1-(3-furyl)hept-2-yn-1-one (SI-2b) was obtained as brown oil (1.53 g,87% isolated yield). TLC (20% EtOAc/hexanes): R_(f)=0.47, visualized byUV absorbance. ¹H NMR (CDCl₃, 500 MHz): δ 8.11 (s, 1H), 7.42 (s, 1H),6.81 (s, 1H), 2.44 (t, J=7.0 Hz, 2H), 1.63 (quintet, J=7.0 Hz, 2H), 1.49(sextet, J=7.5 Hz, 2H), 0.95 (t, J=7.5 Hz, 3H). This spectrum is inagreement with previously reported spectral data.³

1-(4-Bromophenyl)hept-2-yn-1-one (SI-2c) was obtained as dark brown oil(2.31 g, 87% isolated yield). TLC (20% EtOAc/hexanes): R_(f)=0.55,visualized by UV absorbance. ¹H NMR (CDCl₃, 500 MHz): δ 7.98 (d, J=8.5Hz, 2H), 7.62 (d, J=8.0 Hz, 2H), 2.50 (t, J=7.0 Hz, 2H), 1.66 (quintet,J=7.5 Hz, 2H), 1.50 (sextet, J=7.5 Hz, 2H), 0.96 (t, J=7.5 Hz, 3H). Thisspectrum is in agreement with previously reported spectral data.⁴

1-Phenyl-4,4-dimethyl-pent-1-yn-3-one (SI-2d) was obtained as yellow oil(1.35 g, 74% isolated yield). TLC (20% EtOAc/hexanes): R_(f)=0.61,visualized by UV absorbance. ¹H NMR (CDCl₃, 500 MHz): δ 7.59-7.37 (m,5H), 1.28 (s, 9H). This spectrum is in agreement with previouslyreported spectral data.⁵

1-(4-Nitrophenyl)hept-2-yn-1-one (SI-2e) was obtained as reddish orangeoil (1.76 g, 76% isolated yield). TLC (20% EtOAc/hexanes): R_(f)=0.47,visualized by UV absorbance. ¹H NMR (CDCl₃, 600 MHz): δ 8.33-8.28 (m,4H), 2.55 (t, J=7.2 Hz, 2H), 1.69 (quintet, J=7.2 Hz, 2H), 1.51 (sextet,J=7.2 Hz, 2H), 0.98 (t, J=7.2 Hz, 3H). This spectrum is in agreementwith previously reported spectral data.⁶

1-phenyl-3-trimethylsilyl-prop-2-yn-1-one (SI-2f) was obtained as paleyellow oil (1.62 g, 80% isolated yield). TLC (20% EtOAc/hexanes):R_(f)=0.67, visualized by UV absorbance. ¹H NMR (CDCl₃, 500 MHz): δ 8.15(d, J=7.0 Hz, 2H), 7.62 (t, J=7.0 Hz, 1H), 7.49 (t, J=7.0 Hz, 2H), 0.32(s, 9H). This spectrum is in agreement with previously reported spectraldata.⁷

1-(4-Methylphenyl)hept-2-yn-1-one (SI-2g) was obtained as yellow oil(1.70 g, 85% isolated yield). TLC (20% EtOAc/hexanes): R_(f)=0.52,visualized by UV absorbance. ¹H NMR (CDCl₃, 500 MHz): δ 8.03 (d, J=8.5Hz, 2H), 7.27 (d, J=9.0 Hz, 2H), 2.50 (t, J=7.0 Hz, 2H), 2.43 (s, 3H),1.66 (quintet, J=7.5 Hz, 2H), 1.50 (sextet, J=7.5 Hz, 2H), 0.96 (t,J=7.5 Hz, 3H). This spectrum is in agreement with previously reportedspectral data.⁶

1-(4-Fluorophenyl)hept-2-yn-1-one (SI-2h) was obtained as yellow oil(1.51 g, 74% isolated yield). TLC (20% EtOAc/hexanes): R_(f)=0.57,visualized by UV absorbance. ¹H NMR (CDCl₃, 500 MHz): δ 8.17-8.14 (m,2H), 7.15 (t, J=8.5 Hz, 2H), 2.51 (t, J=7.0 Hz, 2H), 1.67 (quintet,J=7.5 Hz, 2H), 1.52 (sextet, J=7.5 Hz, 2H), 0.97 (t, J=7.5 Hz, 3H). Thisspectrum is in agreement with previously reported spectral data.⁸

1-(4-Methoxyphenyl)hept-2-yn-1-one (SI-2i) was obtained as yellow oil(1.74 g, 81% isolated yield). TLC (20% EtOAc/hexanes): R_(f)=0.38,visualized by UV absorbance. ¹H NMR (CDCl₃, 600 MHz): δ 8.10 (d, J=9.0Hz, 2H), 6.94 (d, J=8.4 Hz, 2H), 3.88 (s, 3H), 2.49 (t, J=7.2 Hz, 2H),1.66 (quintet, J=7.2 Hz, 2H), 1.50 (sext, J=7.8 Hz, 2H), 0.96 (t, J=7.2Hz, 3H). This spectrum is in agreement with previously reported spectraldata.⁶

1-(4-Trifluoromethylphenyl)hept-2-yn-1-one (SI-2j) was obtained as darkyellow oil (2.19 g, 87% isolated yield). TLC (20% EtOAc/hexanes):R_(f)=0.48, visualized by UV absorbance. ¹H NMR (CDCl₃, 500 MHz): δ 8.24(d, J=8.0 Hz, 2H), 7.75 (d, J=8.0 Hz, 2H), 2.53 (t, J=7.0 Hz, 2H), 1.68(quintet, J=7.0 Hz, 2H), 1.51 (sext, J=7.5 Hz, 2H), 0.97 (t, J=7.5 Hz,3H). This spectrum is in agreement with previously reported spectraldata.⁴

Methyl 7-oxo-7-phenyl-hept-5-yn-1-oate (SI-2k) was obtained as darkyellow solid (1.95 g, 85% isolated yield). TLC (20% EtOAc/hexanes):R_(f)=0.22, visualized by UV absorbance. ¹H NMR (CDCl₃, 500 MHz): δ 8.12(d, J=8.0 Hz, 2H), 7.61 (t, J=7.5 Hz, 1H), 7.48 (t, J=7.5 Hz, 2H), 3.70(s, 3H), 2.60 (t, J=7.0 Hz, 2H), 2.53 (t, J=7.0 Hz, 2H), 2.01 (quintet,J=7.0 Hz, 2H). ¹³C NMR (CDCl₃, 125 MHz): δ 178.2, 173.3, 136.9, 134.1,129.7, 128.7, 95.1, 80.3, 51.9, 32.8, 23.2, 18.8. HRMS (ESI+) m/z calcdfor C₁₄H₁₄O₃ ([M+Na]⁺) 253.0841, found 253.0832.

B. Preparation of Alkynyl Oxime 1a-k. General Procedure.

Oximes were prepared according to a literature procedure.⁹ Open to air,a 50 mL round bottom flask was charged with H₂NOH.HCl (2.2 equiv),Na₂SO₄ (3.0 equiv), and a stir bar. The solids were suspended in MeOH(20 mL). Pyridine (4.0 equiv) and then ketone SI-2 (1.0 equiv) wereadded. The reaction was allowed to stir at room temperature until thestarting material was consumed completely, as shown by TLC after 5 h.The reaction was quenched with DI water (25 mL) and extracted with EtOAc(3×25 mL). The combined organic layers were washed with brine (25 mL),dried over MgSO₄, filtered, and concentrated in vacuo. The crude waspurified by silica gel flash column chromatography using a stepwisegradient from 5% to 10% EtOAc in hexanes. Product-containing fractionswere combined and concentrated in vacuo to afford 1.

(Z)-1-phenylhept-2-yn-1-one oxime (1a) was obtained as light yellowsolid (38 mg, 22% isolated yield). TLC (20% EtOAc/hexanes): R_(f)=0.30,visualized by UV absorbance. ¹H NMR (d₈-toluene, 500 MHz): δ 9.12 (s,1H), 7.98 (d, J=7.5 Hz, 2H), 7.12-7.05 (m, 3H), 2.16 (t, J=7.0 Hz, 2H),1.37-1.23 (m, 4H), 0.75 (t, J=7.5 Hz, 3H). This spectrum is in agreementwith previously reported spectral data.³

(Z)-1-(3-furyl)hept-2-yn-1-one oxime (1b) was obtained as yellow solid(115 mg, 6.9% isolated yield). TLC (20% EtOAc/hexanes): R_(f)=0.27,visualized by UV absorbance. ¹H NMR (CDCl₃, 500 MHz): δ 7.85 (s, 1H),7.74 (s, 1H), 7.39 (s, 1H), 6.69 (s, 1H), 2.52 (t, J=7.0 Hz, 2H), 1.65(quintet, J=7.0 Hz, 2H), 1.50 (sextet, J=7.5 Hz, 2H), 0.96 (t, J=7.0 Hz,3H). ¹³C NMR (CDCl₃, 125 MHz): δ 143.9, 143.3, 136.0, 122.4, 107.5,102.9, 70.2, 30.4, 22.2, 19.4, 13.7. HRMS (ESI+) m/z calcd for C₁₁H₁₃NO₂([M+Na]⁺) 214.0844, found 214.0849.

(Z)-1-(4-Bromophenyl)hept-2-yn-1-one oxime (1c) was obtained as brownsolid (0.234 g, 9.6% isolated yield). TLC (20% EtOAc/hexanes):R_(f)=0.26, visualized by UV absorbance. ¹H NMR (CDCl₃, 500 MHz): δ 8.34(s, 1H), 7.69 (d, J=8.6 Hz, 2H), 7.51 (d, J=8.6 Hz, 2H), 2.58 (t, J=7.1Hz, 2H), 1.67 (quintet, J=7.1 Hz, 2H), 1.51 (sextet, J=7.5 Hz, 2H), 0.96(t, J=7.4 Hz, 3H). ¹³C NMR (CDCl₃, 125 MHz): δ 141.6, 132.7, 131.7,128.2, 124.3, 106.2, 70.2, 30.4, 22.2, 19.6, 13.7. HRMS (ESI+) m/z calcdfor C₁₃H₁₄BrNO ([M+Na]⁺) 302.0157, found 302.0148.

(Z)-1-Phenyl-4,4-dimethylpent-1-yn-3-one oxime (1d) was obtained aswhite solid (0.863 g, 58% isolated yield). TLC (20% EtOAc/hexanes):R_(f)=0.38, visualized by UV absorbance. ¹H NMR (d₈-toluene, 600 MHz): δ9.58 (s, 1H), 7.37-7.36 (m, 2H), 6.97-6.90 (m, 3H), 1.23 (s, 9H). Thisspectrum is in agreement with previously reported spectral data.³

(Z)-1-(4-Nitrophenyl)hept-2-yn-1-one oxime (1e) was obtained as darkyellow solid (0.112 g, 6.0% isolated yield). TLC (20% EtOAc/hexanes):R_(f)=0.26, visualized by UV absorbance. ¹H NMR (CDCl₃, 600 MHz): δ 8.20(s, 1H), 8.14-8.13 (m, 2H), 7.91-7.89 (m, 2H), 2.50 (t, J=7.2 Hz, 2H),1.59 (quintet, J=7.3 Hz, 2H), 1.42 (sextet, J=7.5 Hz 2H), 0.88 (t, J=7.4Hz, 3H). ¹³C NMR (CDCl₃, 150 MHz): δ 148.6, 140.8, 139.7, 127.4, 123.8,107.2, 69.9, 30.3, 22.2, 19.6, 13.7. HRMS (ESI−) m/z calcd forC₁₃H₁₄N₂O₃ ([M−H]⁻) 245.0926, found 245.0929.

(Z)-1-phenyl-3-trimethylsilyl-prop-2-yn-1-one oxime (1f) was obtained aswhite solid (0.885 g, 51% isolated yield). TLC (20% EtOAc/hexanes):R_(f)=0.41, visualized by UV absorbance. ¹H NMR (CDCl₃, 500 MHz): δ 8.11(s, 1H), 7.83-7.81 (m, 2H), 7.40-7.39 (m, 3H), 0.33 (s, 9H). ¹³C NMR(CDCl₃, 125 MHz): δ 142.1, 133.1, 130.1, 128.6, 126.6, 110.4, 92.7,−0.19. HRMS (ESI+) m/z calcd for C₁₂H₁₅NOSi ([M+Na]⁺) 240.0821, found240.0815.

(Z)-1-(4-Methylphenyl)hept-2-yn-1-one oxime (1g) was obtained as lightyellow solid (0.347 g, 19% isolated yield). TLC (20% EtOAc/hexanes):R_(f)=0.34, visualized by UV absorbance. ¹H NMR (CDCl₃, 500 MHz): δ 8.49(s, 1H), 7.71 (d, J=8.2 Hz, 2H), 7.19 (d, J=8.2 Hz, 2H), 2.58 (t, J=7.1Hz, 2H), 2.37 (s, 3H), 1.68 (quintet, J=7.3 Hz, 2H), 1.52 (sextet, J=7.5Hz, 2H), 0.97 (t, J=7.3 Hz, 3H). ¹³C NMR (CDCl₃, 125 MHz): δ 142.4,140.1, 131.0, 129.5, 126.6, 105.5, 70.7, 30.5, 22.2, 21.5, 19.6, 13.7.HRMS (ESI+) m/z calcd for C₁₄H₁₇NO ([M+Na]⁺) 238.1208, found 238.1200.

(Z)-1-(4-Fluorophenyl)hept-2-yn-1-one oxime (1h) was obtained as yellowoil (0.178 g, 11% isolated yield). TLC (20% EtOAc/hexanes): R_(f)=0.29,visualized by UV absorbance. ¹H NMR (CDCl₃, 400 MHz): δ 8.02 (s, 1H),7.83-7.80 (m, 2H), 7.07 (t, J=8.4 Hz, 2H), 2.58 (t, J=7.2 Hz, 2H), 1.68(quintet, J=7.2 Hz, 2H), 1.53 (sextet, J=7.6 Hz, 2H), 0.97 (t, J=7.6 Hz,3H). ¹³C NMR (CDCl₃, 125 MHz): δ 164.9, 162.9, 141.5, 129.85, 129.82,128.57, 128.50, 115.65, 115.48, 106.0, 70.3, 30.4, 22.2, 19.6, 13.7. ¹⁹FNMR (CDCl₃, 376 MHz): δ −111.2. HRMS (ESI+) m/z calcd for C₁₃H₁₄FNO([M+Na]⁺) 242.0957, found 242.0957.

(Z)-1-(4-Methoxyphenyl)hept-2-yn-1-one oxime (1i) was obtained as yellowsolid (0.318 g, 17% isolated yield). TLC (20% EtOAc/hexanes):R_(f)=0.19, visualized by UV absorbance. ¹H NMR (CDCl₃, 600 MHz): δ 8.15(s, 1H), 7.77-7.76 (m, 2H), 6.91-6.89 (m, 2H), 3.84 (s, 3H), 2.57 (t,J=7.1 Hz, 2H), 1.67 (quintet, J=7.2 Hz, 2H), 1.51 (sextet, J=7.6 Hz,2H), 0.97 (t, J=7.4 Hz, 3H). ¹³C NMR (CDCl₃, 125 MHz): δ 161.1, 142.1,128.1, 126.4, 113.9, 105.4, 70.6, 55.5, 30.5, 22.2, 19.6, 13.7. HRMS(ESI+) m/z calcd for C₁₄H₁₇NO₂ ([M+Na]⁺) 254.1157, found 254.1158.

(Z)-1-(4-Trifluoromethylphenyl)hept-2-yn-1-one oxime (1j) was obtainedas light brown solid (0.262 g, 11% isolated yield). TLC (20%EtOAc/hexanes): R_(f)=0.32, visualized by UV absorbance. ¹H NMR (CDCl₃,500 MHz): δ 8.26 (s, 1H), 7.94 (d, J=8.0 Hz, 2H), 7.64 (d, J=8.0 Hz,2H), 2.59 (t, J=7.5 Hz, 2H), 1.68 (quintet, J=7.0 Hz, 2H), 1.52 (sextet,J=7.5 Hz, 2H), 0.97 (t, J=7.5 Hz, 3H). ¹³C NMR (CDCl₃, 125 MHz): δ141.1, 137.0, 131.7, 131.5, 126.9, 125.5 (q, J=15 Hz), 123.0, 106.6,70.0, 30, 4, 22.2, 19.6, 13.7. ¹⁹F NMR (CDCl₃, 376 MHz): δ −62.8. HRMS(ESI+) m/z calcd for C₁₄H₁₄F₃NO ([M+Na]⁺) 292.0925, found 292.0920.

Methyl 7-hydroxyimino-7-phenylhept-5-yn-1-oate (1k) was obtained aslight yellow solid (0.175 g, 8.4% isolated yield). TLC (20%EtOAc/hexanes): R_(f)=0.21, visualized by UV absorbance. ¹H NMR (CDCl₃,500 MHz): δ 8.51 (s, 1H), 7.82-7.80 (m, 2H), 7.39-7.38 (m, 3H), 3.69 (s,3H), 2.66 (t, J=7.0 Hz, 2H), 2.56 (t, J=7.5 Hz, 2H), 2.02 (quintet,J=7.0 Hz, 2H). ¹³C NMR (CDCl₃, 125 MHz): δ 173.5, 133.5, 130.0, 129.0128.6, 126.6, 103.9, 85.6, 51.9, 32.9, 23.6, 19.3. HRMS (ESI+) m/z calcdfor C₁₄H₁₅NO₃ ([M+Na]⁺) 268.0950, found 268.0951.

C. Preparation of IPrAuTFA Catalyst.

No precautions were taken to exclude air or water. The reaction wasconducted in a fume hood with the light turned off. A solution ofIPrAuCl 17 (124 mg, 200. μmol, 1.00 equiv) in DCM (2.0 mL) was added toa dram vial containing AgTFA SI-3 (48.6 mg, 220. μmol, 1.10 equiv) and astirbar. A white precipitation was observed. The vial was capped andwrapped with aluminum foil to protect the reaction mixture from light.The reaction was stirred vigorously at 25° C. for 7 h. The resultingsuspension was then filtered through a Celite plug (ca. 0.5 mL). TheCelite was rinsed with additional DCM (3×0.5 mL), and the resultingsolution was concentrated in vacuo to a a white solid. The solid wascrushed to a fine powder, from which volatiles were removed at 25° C.and ca. 10 mTorr for 18 h to afford IPrAuTFA 12 as a white powder (135mg, 97% isolated yield). ¹H NMR (CDCl₃, 500 MHz): δ 7.53 (t, J=7.8 Hz,2H), 7.31 (d, J=7.8 Hz, 4H), 7.21 (s, 2H), 2.53 (sept, J=7.0 Hz, 4H),1.35 (d, J=7.0 Hz, 12H), 1.23 (d, J=7.0 Hz, 12H). ¹⁹F NMR (CDCl₃, 376MHz): δ −74.1 (s). This spectrum is in agreement with previouslyreported spectral data.¹⁰

D. Optimization of Oxyboration Reaction Conditions.

Boric ester 2a. The reaction was performed inside N₂-filled glovebox. A4-dram vial was charged with a solution of 1a (20.1 mg, 0.100 mmol, 1.00equiv) in d₈-toluene (0.30 mL). To this solution was addedcatecholborane (10.7 μL, 0.100 mmol, 1.00 equiv) at 25° C. The reactionmixture was stirred for 30 min during which the evolution of H₂ gas wasobserved, to afford 2a, which was used directly in the screen ofreaction conditions without further purification.

¹H NMR (d₈-toluene, 600 MHz): δ 8.10-8.09 (m, 2H), 7.12-7.10 (m, 3H),6.91-6.90 (m, 2H), 6.72 (dd, J=5.3, 3.4 Hz, 2H), 2.12 (t, J=6.8 Hz, 2H),1.35-1.28 (m, 4H), 0.79 (t, J=7.1 Hz, 3H).

¹¹B NMR (d₈-toluene, 600 MHz): δ 25.4 (s).

Boronic ester 3a. Catalyst was dissolved in d₈-toluene (0.2 mL) andadded to the dram vial containing 2a. After mixing thoroughly, thereaction mixture was transferred to a J. Young NMR tube, which wascapped and removed from the glovebox. The tube was heated in a preheatedoil bath at the temperature listed in Table SI-1. After heating for theindicated time, the progress of the reaction was monitored by ¹H and ¹¹BNMR spectroscopy.

¹H NMR (d₈-toluene, 600 MHz): δ 7.92-7.90 (m, 2H), 7.26-7.19 (m, 3H),6.92-6.90 (m, 2H), 3.26 (s, 3H), 6.76-6.74 (m, 2H), 2.97 (t, J=7.6 Hz,2H), 1.64 (quintet, J=7.5 Hz, 2H), 1.28 (sextet, J=7.4 Hz, 2H), 0.84 (t,J=7.2 Hz, 3H).

¹¹B NMR (d₈-toluene, 600 MHz): δ 31.2 (s).

TABLE SI-1 Example 4. Optimization of oxyboration reaction conditions by¹H NMR spectroscopy Reaction ¹H NMR Temperature Cat. loading timeyield^(a) 3a Entry Catalyst (° C.) (% mol) (h) (%) 1 IPrAuTFA 25 10 2289 2 IPrAuTFA 50 10 2 92 3 IPrAuTFA 50 5.0 2 90 4 IPrAuTFA 50 2.5 6 90 5IPrAuTFA 50 1.0 23 85 6 IPrAuCl 50 2.5 6 0 7 IPrAuOTs 50 2.5 6 34 8 AuCl50 2.5 6 0 9 AuCl₃ 50 2.5 6 0 10 IPrOAc 50 2.5 6 0 11 NaTFA 50 10 18 0^(a)Determined by ERECTIC using mesitylene as external standard

E. General Procedure NMR Conversions Using ERECTIC.

In a N₂-filled glovebox, an alkynyloxime (0.10 mmol, 1.0 equiv) wasdissolved in 0.3 mL d₈-toluene in a 4-dram vial equipped with stir bar.Catecholborane (10.7 μL, 0.100 mmol, 1.00 equiv) was added via gastightsyringe to the solution above. The resulting solution was allowed tostir at room temperature for 0.5 h. The catalyst IPrAuTFA (1.8 mg,0.0025 mmol, 2.5 mol %) was dissolved in 0.2 mL d₈-toluene andtransferred via syringe to the solution above. This mixture was thentransferred into a J. Young NMR tube, which was sealed and removed fromthe glove box. Reaction progress was monitored by ¹H NMR spectroscopy(600 MHz, d₈-toluene) of 3 using the ERECTIC method relative to externalmesitylene standard (252 mmol/L in d₈-toluene). This general procedurewas used for R₁=Ph, R₂=nBu (3a, 90%, 6 h, 50° C.); R₁=3-furyl, R₂=nBu(3b, 85%, 24 h, 50° C.); R₁=4-BrPh, R₂=nBu (3c, 93%, 6 h, 50° C.);R₁=t-Bu, R₂=Ph (3d, 95%, 4 h, 110° C.); R₁=4-NO₂Ph, R₂=nBu (3e, 90%, 6h, 50° C.); R₁=Ph, R₂=TMS (3f, 87%, 24 h, 90° C.); R₁=4-MePh, R₂=nBu(3g, 95%, 6 h, 50° C.); R₁=4-FPh, R₂=nBu (3h, 92%, 6 h, 50° C.);R₁=4-MeOPh, R₂=nBu (3i, 92%, 24 h, 60° C.); R₁=4-CF₃Ph, R₂=nBu (3j, 98%,6 h, 50° C.); R₁=Ph, R₂=(CH₂)₃CO₂Me (3k, 94%, 8 h, 50° C.).

F. Synthesis of Pinacol Boronates 4: General Procedure.

In a N₂-filled glovebox, oxime 1 (0.50 mmol, 1.0 equiv) was dissolved in1.5 mL toluene in a 20-dram vial equipped with stir bar. Catecholborane(53.5 μL, 0.500 mmol, 1.00 equiv) was added via gastight syringe to thesolution above. The resulting solution was allowed to stir at roomtemperature for 0.5 h. The catalyst IPrAuTFA (8.8 mg, 0.012 mmol, 2.5mol %) was dissolved in 1.0 mL toluene and transferred via syringe tothe solution above in a capped vial and the resulting suspension wasstirred in a pre-heated copper shot heating bath at appropriatetemperature and time. The reaction mixture was then cooled to roomtemperature and a solution of PPh₃ (6.6 mg, 0.025 mmol, 5.0 mol %) intoluene (3.0 mL) was added. The resulting suspension was stirred for 20h at room temperature in order to quench IPrAuTFA before proceeding.

Pinacol (177 mg, 1.50 mmol, 3.00 equiv) was dissolved in anhydrous Et₃N(1.04 mL, 7.50 mmol, 15.0 equiv). The resulting solution was added tothe quenched reaction mixture, and the resulting suspension was stirredat 25° C. for 1 h. The reaction mixture was then removed from theglovebox. Volatiles were removed in vacuo. The resulting light brown oilwas purified by silica gel chromatography using an elution gradient from100% hexanes to 100% CH₂Cl₂. Solvents were removed in vacuo to affordthe desired pinacol boronate 4. All of the pinacol boronates 4a-4k aremissing one carbon signal in the ¹³C NMR spectroscopy data. This carbonatom is assigned to the carbon in the newly formed C—B a bond. This isexpected due to the quadrupolar relaxation of B.¹¹

Pinacol boronate (4a) was obtained as clear oil at 50° C. after 6 h(0.123 g, 75% isolated yield). TLC (40% CH₂Cl₂/hexanes): R_(f)=0.10,visualized by UV absorbance. ¹H NMR (CDCl₃, 600 MHz): δ 7.82-7.80 (m,2H), 7.41-7.40 (m, 3H), 3.00 (t, J=7.8 Hz, 2H), 1.73 (quintet, J=7.8 Hz,2H), 1.40 (sextet, J=7.8 Hz, 2H), 1.30 (s, 12H), 0.95 (t, J=7.2 Hz, 3H).¹³C NMR (CDCl₃, 125 MHz): δ 182.8, 166.1, 130.3, 129.4, 129.1, 128.1,83.7, 30.7, 27.0, 24.9, 22.4, 13.8. ¹¹B NMR (CDCl₃, 192 MHz): δ 29.9(s). HRMS (ESI+) m/z calcd for C₁₉H₂₆BNO₃ ([M+Na]⁺) 350.1907, found350.1903.

Pinacol boronate (4b) was obtained as clear oil at 50° C. after 24 h(0.113 g, 71% isolated yield). TLC (40% CH₂Cl₂/hexanes): R_(f)=0.09,visualized by UV absorbance. ¹H NMR (CDCl₃, 500 MHz): δ 8.43 (s, 1H),7.45-7.44 (m, 1H), 6.96 (s, 1H), 3.00 (t, J=7.5 Hz, 2H), 1.69 (quintet,J=7.5 Hz, 2H), 1.37 (sextet, J=7.5 Hz, 2H), 1.34 (s, 12H), 0.93 (t,J=7.5 Hz, 3H). ¹³C NMR (CDCl₃, 125 MHz): δ 183.6, 158.5, 144.3, 142.9,116.3, 109.7, 83.8, 30.6, 26.8, 25.0, 22.3, 13.8. ¹¹B NMR (CDCl₃, 192MHz): δ 29.6 (s). HRMS (ESI+) m/z calcd for C₁₇H₂₄BNO₄ ([M+Na]⁺)340.1699, found 340.1691.

Pinacol boronate (4c) was obtained as yellow solid at 50° C. after 6 h(0.131 g, 65% isolated yield). TLC (40% CH₂Cl₂/hexanes): R_(f)=0.09,visualized by UV absorbance. ¹H NMR (CDCl₃, 500 MHz): δ 7.71 (d, J=8.5Hz, 2H), 7.53 (d, J=8.5 Hz, 2H), 3.00 (t, J=7.5 Hz, 2H), 1.71 (quintet,J=7.5 Hz, 2H), 1.41 (sextet, J=7.0 Hz, 2H), 1.30 (s, 12H), 0.95 (t,J=7.0 Hz, 3H). ¹³C NMR (CDCl₃, 125 MHz): δ 183.3, 165.2, 131.3, 130.7,129.3, 123.8, 83.8, 30.6, 27.0, 24.9, 22.3, 13.8. ¹¹B NMR (CDCl₃, 192MHz): δ 29.7 (s). HRMS (ESI+) m/z calcd for C₁₉H₂₅BBrNO₃ ([M+H]⁺)408.1175, found 408.1163.

Pinacol boronate (4d) was obtained as white solid at 110° C. after 4 h(0.154 g, 94% isolated yield). TLC (40% CH₂Cl₂/hexanes): R_(f)=0.11,visualized by UV absorbance. ¹H NMR (CDCl₃, 600 MHz): δ 7.78-7.76 (m,2H), 7.42-7.41 (m, 3H), 1.44 (s, 9H), 1.34 (s, 12H). ¹³C NMR (CDCl₃, 125MHz): δ 175.4, 174.7, 130.1, 129.1, 128.3, 125.8, 84.3, 33.4, 29.5,25.1. ¹¹B NMR (CDCl₃, 192 MHz): δ 30.5 (s). HRMS (ESI+) m/z calcd forC₁₉H₂₆BNO₃ ([M+H]⁺) 328.2088, found 328.2091.

Pinacol boronate (4e) was obtained as light yellow solid at 50° C. after6 h (0.112 g, 60% isolated yield). TLC (40% CH₂Cl₂/hexanes): R_(f)=0.10,visualized by UV absorbance. ¹H NMR (CDCl₃, 500 MHz): δ 8.27 (d, J=9.0Hz, 2H), 8.03 (d, J=8.5 Hz, 2H), 3.04 (t, J=7.5 Hz, 2H), 1.73 (quintet,J=7.0 Hz, 2H), 1.40 (sextet, J=7.0 Hz, 2H), 1.31 (s, 12H), 0.96 (t,J=7.5 Hz, 3H). ¹³C NMR (CDCl₃, 125 MHz): δ 184.0, 164.4, 148.5, 136.8,130.1, 123.3, 84.0, 30.6, 27.0, 24.9, 22.3, 13.8. ¹¹B NMR (CDCl₃, 192MHz): δ 29.5 (s). HRMS (ESI+) m/z calcd for C₁₉H₂₅BN₂O₅ ([M+Na]⁺)395.1758, found 395.1760.

Pinacol boronate (4f) was obtained as white solid at 90° C. after 24 h(0.122 g, 71% isolated yield). TLC (40% CH₂Cl₂/hexanes): R_(f)=0.15,visualized by UV absorbance. ¹H NMR (CDCl₃, 500 MHz): δ 7.78-7.76 (m,2H), 7.41-7.40 (m, 3H), 1.30 (s, 12H), 0.43 (s, 9H). This spectrum is inagreement with previously reported spectral data.¹²

Pinacol boronate (4g) was obtained as light yellow solid at 50° C. after6 h (0.128 g, 75% isolated yield). TLC (40% CH₂Cl₂/hexanes): R_(f)=0.14,visualized by UV absorbance. ¹H NMR (CDCl₃, 500 MHz): δ 7.71 (d, J=8.0Hz, 2H), 7.21 (d, J=8.0 Hz, 2H), 2.99 (t, J=7.5 Hz, 2H), 2.39 (s, 3H),1.72 (quintet, J=7.5 Hz, 2H), 1.39 (sextet, J=7.5 Hz, 2H), 1.30 (s,12H), 0.95 (t, J=7.5 Hz, 3H). ¹³C NMR (CDCl₃, 125 MHz): δ 182.7, 166.0,139.3, 128.92, 128.87, 127.4, 83.7, 30.7, 27.0, 24.9, 22.4, 21.5, 13.8.¹¹B NMR (CDCl₃, 192 MHz): δ 29.9 (s). HRMS (ESI+) m/z calcd forC₂₀H₂₈BNO₃ ([M+H]⁺) 342.2244, found 342.2241.

Pinacol boronate (4h) was obtained as clear oil at 50° C. after 6 h(0.115 g, 67% isolated yield). TLC (40% CH₂Cl₂/hexanes): R_(f)=0.11,visualized by UV absorbance. ¹H NMR (CDCl₃, 500 MHz): δ 7.83-7.80 (m,2H), 7.09 (t, J=8.7 Hz, 2H), 3.00 (t, J=7.5 Hz, 2H), 1.72 (quintet,J=7.4 Hz, 2H), 1.40 (sextet, J=7.5 Hz, 2H), 1.30 (s, 12H), 0.95 (t,J=7.3 Hz, 3H). ¹³C NMR (CDCl₃, 125 MHz): δ 183.2, 165.3, 164.7, 162.7,131.0, 126.4, 115.1, 83.8, 30.6, 27.0, 24.9, 22.4, 13.8. ¹¹B NMR (CDCl₃,192 MHz): δ 29.8 (s). ¹⁹F NMR (CDCl₃, 376 MHz): δ −112.3. HRMS (ESI+)m/z calcd for C₁₉H₂₅BFNO₃ ([M+Na]⁺) 368.1813, found 368.1802.

Pinacol boronate (4i) was obtained as off white solid at 60° C. after 24h (0.132 g, 74% isolated yield). TLC (40% CH₂Cl₂/hexanes): R_(f)=0.23,visualized by UV absorbance. ¹H NMR (CDCl₃, 600 MHz): δ 7.79 (d, J=8.8Hz, 2H), 6.92 (d, J=8.8 Hz, 2H), 3.83 (s, 3H), 2.99 (t, J=7.5 Hz, 2H),1.72 (quintet, J=7.6 Hz, 2H), 1.39 (sextet, J=7.4 Hz, 2H), 1.30 (s,12H), 0.95 (t, J=7.3 Hz, 3H). ¹³C NMR (CDCl₃, 125 MHz): δ 182.8, 165.7,160.6, 130.4, 122.8, 113.5, 83.7, 55.4, 30.7, 27.0, 24.9, 22.4, 13.8.¹¹B NMR (CDCl₃, 192 MHz): δ 29.8 (s). HRMS (ESI+) m/z calcd forC₂₀H₂₈BNO₄ ([M+Na]⁺) 380.2013, found 380.2002.

Pinacol boronate (4j) was obtained as off white solid at 50° C. after 6h (0.110 g, 56% isolated yield). TLC (40% CH₂Cl₂/hexanes): R_(f)=0.15,visualized by UV absorbance. ¹H NMR (CDCl₃, 600 MHz): δ 7.96 (d, J=8.4Hz, 2H), 7.66 (d, J=8.4 Hz, 2H), 3.03 (t, J=7.8 Hz, 2H), 1.73 (quintet,J=7.2 Hz, 2H), 1.41 (sextet, J=7.8 Hz, 2H), 1.30 (s, 12H), 0.96 (t,J=7.8 Hz, 3H). ¹³C NMR (CDCl₃, 125 MHz): δ 183.6, 165.1, 133.9, 131.4,131.2, 129.5, 125.1 (q, J=15.5 Hz), 123.2, 83.9, 30.6, 27.0, 24.9, 22.4,13.8. ¹¹B NMR (CDCl₃, 192 MHz): δ 29.7 (s). ¹⁹F NMR (CDCl₃, 376 MHz): δ−62.7. HRMS (ESI+) m/z calcd for C₂₀H₂₅BF₃NO₃ ([M+H]⁺) 396.1962, found396.1970.

Pinacol boronate (4k) was obtained as clear oil at 50° C. after 8 h(0.119 g, 64% isolated yield). TLC (100% CH₂Cl₂): R_(f)=0.28, visualizedby UV absorbance. ¹H NMR (CDCl₃, 600 MHz): δ 7.81-7.80 (m, 2H),7.42-7.38 (m, 3H), 3.67 (s, 3H), 3.07 (t, J=7.8 Hz, 2H), 2.40 (t, J=7.8Hz, 2H), 2.09 (quintet, J=7.2 Hz, 2H), 1.30 (s, 12H). ¹³C NMR (CDCl₃,125 MHz): δ 181.4, 173.5, 16.2, 130.0, 129.5, 129.1, 128.1, 83.9, 51.7,33.3, 26.6, 24.9, 23.6. ¹¹B NMR (CDCl₃, 192 MHz): δ 29.7 (s). HRMS(ESI+) m/z calcd for C₂₀H₂₆BNO₅ ([M+H]⁺) 372.1986, found 372.1983.

G. Uncatalyzed Oxyboration.

In a N₂-filled glovebox, oxime 1 (0.10 mmol, 1.0 equiv) was dissolved in0.5 mL d₈-toluene in a 4-dram vial equipped with stir bar.Catecholborane (10.7 μL, 0.100 mmol, 1.00 equiv) was added via gastightsyringe to the solution above. The resulting solution was allowed tostir at room temperature for 0.5 h. The reaction mixture was transferredvia syringe to a J. Young NMR tube, removed from the glovebox, andheated in a preheated oil bath at 110° C. until full consumption ofstarting materials was achieved, after which the ¹H NMR yields wererecorded. The ¹H NMR yields were determined by the ERECTIC method usingmesitylene as the external standard.

TABLE SI-2 Example 4. Uncatalyzed Oxyboration Uncatalyzed R¹/R² ¹H NMRyield Time 3a Ph/Bu 89% 111 h 3b 3-Furyl/Bu 68% 18 days 3c 4-BrPh/Bu 91%20 h 3d t-Bu/Ph 24% 7 days 3e 4-NO₂Ph/Bu 84% 20 h 3f Ph/TMS 0% 48 h 3g4-MePh/Bu 78% 15 days 3h 4-FPh/Bu 87% 65 h 3i 4-MeO/Bu 90% 65 h 3j4-CF₃Ph/Bu 74% 21 days 3k Ph/(CH₂)₃CO₂Me 83% 52 h

H. General Procedure for HRMS Detection of Reaction Intermediates.

In a N₂-filled glovebox, alkynyloxime 1c (28.0 mg, 0.100 mmol, 1.00equiv) was dissolved in 0.3 mL d₈-toluene in a 4-dram vial equipped withstir bar. Catecholborane (10.7 μL, 0.100 mmol, 1.00 equiv) was added viagastight syringe to the solution above. The resulting solution wasallowed to stir at room temperature for 0.5 h. The catalyst IPrAuTFA(1.8 mg, 0.0025 mmol, 2.5 mol %) was dissolved in 0.2 mL toluene andtransferred via syringe to the solution above. The vial was capped andthe resulting suspension was stirred in a pre-heated 50° C. copper shotheating bath for 30 min. An aliquot of the reaction mixture waswithdrawn into a Hamilton 1700 Series Gastight Syringes N Termination(250 μL, N, Gauge: 22 s, 2 in., Point style: 3), the tip was placed in aseptum as a cap before removing from the glovebox. The sample-containingsyringe was quickly carried to the HRMS instrument and injected usingESI technique in positive and negative modes. Due to the extremely highair and moisture sensitivity of the reaction components, no masscalibration was done.

I. Synthesis of Organogold Intermediate 7a.

(Z)-1-phenylhept-2-yn-1-one oxime ether (SI-4) was prepared according toa literature procedure.¹³ In N₂-filled glovebox, a 50 mL round bottomflask was charged with H₂NOMe.HCl (418 mg, 10.0 mmol, 2.00 equiv),Na₂SO₄ (1.42 g, 10.0 mmol, 2.00 equiv), and a stir bar. The solids weresuspended in MeOH (15 mL). Pyridine (1.50 mL, 18.5 mmol, 3.70 equiv) andthen ketone SI-2a (0.93 g, 5.0 mmol, 1.0 equiv) were added. The reactionwas allowed to stir at 25° C. for 19 h. The reaction was quenched with30 mL DI water and extracted with EtOAc (3×30 mL). The combined organiclayers were washed with brine (30 mL), dried over MgSO₄, filtered, andconcentrated in vacuo. The crude was purified by silica gel flash columnchromatography using a stepwise gradient from 5% to 10% EtOAc inhexanes. Product-containing fractions were combined and concentrated invacuo to afford SI-4 as light yellow oil (0.53 g, 49% isolated yield).TLC (40% CH₂Cl₂/hexanes): R_(f)=0.43, visualized by UV absorbance. ¹HNMR (CDCl₃, 500 MHz) b: 7.84-7.82 (m, 2H), 7.37-7.36 (m, 3H), 4.08 (s,3H), 2.55 (t, J=7.5 Hz, 2H), 1.66 (quintet, J=7.5 Hz, 2H), 1.50 (sextet,J=7.5 Hz, 2H), 0.96 (t, J=7.5 Hz, 3H). This spectrum is in agreementwith previously reported spectral data.¹⁴

Organogold intermediate (7a) was prepared according to a litprocedure.¹³ In a N₂-filled glovebox, alkynyloxime ether SI-4 (43.0 mg,0.20 mmol, 1.00 equiv) was dissolved in 1.0 mL anhydrous CH₃CN in a4-dram vial equipped with stir bar. The resulting solution wastransferred into a vial containing IPrAuCl (124 mg, 0.200 mmol, 1.00equiv) and AgOTs (55.8 mg, 0.200 mmol, 1.00 equiv), allowed to stir at25° C. for 24 h. The resulting suspension was filtered, washed withanhydrous CH₃CN (3×1 ml). The precipitate was dissolved in anhydrousCH₂Cl₂, filtered, and the filtrates were combined. The solvents wereremoved in vacuo to afford the crude product as a white solid. The crudeproduct was recrystallized with CH₃CN at −35° C. for two days. Thepurified product was filtered to afford a white solid (89.8 mg, 57%isolated yield). ¹H NMR (d₈-toluene, 600 MHz): δ 8.14 (d, J=7.9 Hz, 2H),7.28 (t, J=7.8 Hz, 2H), 7.15 (t, J=7.4 Hz, 1H), 7.06 (d, J=7.8 Hz, 4H),7.00 (t, J=7.7 Hz, 2H), 6.44 (s, 2H), 2.60 (quintet, J=6.9 Hz, 4H), 2.40(t, J=7.4 Hz, 2H), 1.43 (quintet, J=7.6 Hz, 2H), 1.29 (d, J=6.9 Hz,12H), 1.19 (sextet, J=7.6 Hz, 2H), 1.06 (d, J=6.9 Hz, 12H), 0.86 (t,J=7.3 Hz, 3H). ¹³C NMR (d₈-toluene, 150 MHz): δ 197.1, 178.0, 169.4,146.0, 135.4, 135.1, 130.7, 129.6, 128.1, 127.1, 124.3, 122.9, 32.2,29.5, 29.1, 24.6, 23.9, 22.8.

J. Organogold-to-Boron Transmetalation Stoichiometric Study.

In a N₂-filled glovebox, B-chlorocatecholborane 15 (3.1 mg, 0.020 mmol,1.0 equiv) was dissolved in d₈-toluene (0.4 mL). The resulting solutionwas transferred via pipette to a 4-dram vial containing organogoldcomplex 7a (15.7 mg, 0.0200 mmol, 1.00 equiv). The resulting mixture wastransferred via pipette to a J. Young NMR tube, which was capped andremoved from the glovebox. An off-white precipitate started to form veryearly in the reaction mixture. ¹H and ¹¹B NMR spectra were acquired att=10 min. Then the sample was heated in a preheated oil bath at 50° C.The progress of the reaction was monitored by ¹H and ¹¹B NMRspectroscopy. After 2 h, the reaction was complete and boronic ester 3awas afforded in 96% NMR yield, determined by ERECTIC method withmesitylene as the external standard. For comparison and to facilitateanalysis, the ¹H NMR stacked plot image in Scheme 3 was made bycombining the independent ¹H NMR spectra of the organogold complex 7aand B-chlorocatecholborane in two separate NMR spectroscopy samples(before mixing) into the top most line in the image. The spectrum to theleft of the break is from complex 7a and to the right of the break isfrom B-chlorocatecholborane. The ppm scale for the x-axis was identicalfor all four spectra included in this stack plot.

K. Crossover Experiment.

3,5-di-t-butylcatechol boric ester 18. In a N₂-filled glovebox,alkynyloxime 1c (28.0 mg, 0.100 mmol, 1.00 equiv) was dissolved in 0.3mL d₈-toluene in a 4-dram vial equipped with stir bar.3,5-Di-t-butylcatecholborane (23.2 mg, 0.100 mmol, 1.00 equiv) was addedvia gastight syringe to the solution above. The resulting solution wasallowed to stir at room temperature for 0.5 h.

¹H NMR (d₈-toluene, 600 MHz): δ 7.78 (bs, 2H), 7.15 (d, J=8.4 Hz, 2H),7.08-7.07 (m, 2H), 2.10 (t, J=6.6 Hz, 2H), 1.44 (s, 9H), 1.33-1.28 (m,4H), 1.23 (s, 9H), 0.80 (t, J=7.0 Hz, 3H).

¹¹B NMR (d₈-toluene, 600 MHz): δ 25.5 (s).

3,5-di-t-butylcatechol boronic ester 20. In order to acquire anauthentic ¹H NMR spectrum of one of the expected products in thecrossover experiment, IPrAuTFA (1.8 mg, 0.0025 mmol, 2.5 mol %) wasdissolved in 0.2 mL d₈-toluene and transferred via syringe to the dramvial containing 18. After mixing thoroughly, the reaction mixture wastransferred to a J. Young NMR tube, which was capped and removed fromthe glovebox, and heated in a preheated oil bath at 50° C. The progressof the reaction was monitored by ¹H and ¹¹B NMR spectroscopy. After 6 h,55.6% conversion was observed.

¹H NMR (d₈-toluene, 600 MHz): δ 7.64 (d, J=6.6 Hz, 2H), 7.36 (d, J=6.6Hz, 2H), 7.13-7.12 (m, 2H), 3.02 (t, J=7.7 Hz, 2H), 1.68 (quintet, J=7.7Hz, 2H), 1.46 (s, 9H), 1.32-1.30 (m, 2H), 1.25 (s, 9H), 0.86 (t, J=7.4Hz, 3H).

¹¹B NMR (d₈-toluene, 600 MHz): δ 30.2 (s).

3,5-di-t-butylcatechol boric ester 19. In a N₂-filled glovebox,alkynyloxime 1a (20.1 mg, 0.100 mmol, 1.00 equiv) was dissolved in 0.3mL d₈-toluene in a 4-dram vial equipped with stir bar.3,5-Di-t-butylcatecholborane (23.2 mg, 0.100 mmol, 1.00 equiv) was addedvia gastight syringe to the solution above. The resulting solution wasallowed to stir at room temperature for 0.5 h.

¹H NMR (d₈-toluene, 600 MHz): δ 8.10 (bs, 1H), 7.13-7.10 (m, 3H),7.08-7.06 (m, 2H), 2.12 (t, J=6.7 Hz, 2H), 1.44 (s, 9H), 1.35-1.29 (m,4H), 1.23 (s, 9H), 0.79 (t, J=7.1 Hz, 3H).

¹¹B NMR (d₈-toluene, 600 MHz): δ 25.5 (s).

3,5-di-t-butylcatechol boronic ester 21. In order to acquire anauthentic ¹H NMR spectrum of one of the expected products in thecrossover experiment, IPrAuTFA (1.8 mg, 0.0025 mmol, 2.5 mol %) wasdissolved in 0.2 mL d₈-toluene and transferred via syringe to the dramvial containing 19. After mixing thoroughly, the reaction mixture wastransferred to a J. Young NMR tube, which was capped and removed fromthe glovebox, and heated in a preheated oil bath at 50° C. The progressof the reaction was monitored by ¹H and ¹¹B NMR spectroscopy. After 6 h,37.8% conversion was observed.

¹H NMR (d₈-toluene, 600 MHz): δ 7.94 (d, J=7.6 Hz, 2H), 7.26-7.25 (m,2H), 7.13-7.12 (m, 2H), 3.03 (t, J=7.8 Hz, 2H), 1.69 (quintet, J=7.6 Hz,2H), 1.38 (s, 9H), 1.37-1.35 (m, 2H), 1.23 (s, 9H), 0.85 (t, J=7.4 Hz,3H).

¹¹B NMR (d₈-toluene, 600 MHz): δ 30.3 (s).

Crossover Experiment. In a N₂-filled glovebox, boric ester 2a (0.050mmol, 1.0 equiv) and 18 (0.050 mmol, 1.0 equiv) were synthesized in twoseparate 4-dram vials according to the procedures described above ind₈-toluene (0.2 mL each). The catalyst IPrAuTFA (1.8 mg, 0.0025 mmol,2.5 mol %) was dissolved in 0.1 mL d₈-toluene in a separate 4-dram vial.All three solutions were mixed thoroughly and transferred to a J. YoungNMR tube, removed from the glovebox, and heated in a preheated oil bathat 50° C. The progress of the reaction was monitored by ¹H and ¹¹B NMRspectroscopy. The NMR spectroscopy data indicated the presence of allfour products (non-crossover products 3a and 20, and crossover products21 and 3c).

Establishing That the Crossover Products Formed through Preequilibrium.In a N₂-filled glovebox, boric ester 2a (0.050 mmol, 1.0 equiv) and 11(0.050 mmol, 1.0 equiv) were synthesized in two separate 4-dram vialsaccording to the procedures described above in d₈-toluene (0.2 mL each).All two solutions were mixed thoroughly and transferred to a J. YoungNMR tube, removed from the glovebox. The progress of the reaction wasmonitored by ¹H and ¹¹B NMR spectroscopy. ¹H NMR spectroscopy indicateda rapid interconversion between 2a and 18 to form a mixture of fourboric esters 2a, 18, 19, and 2c in a 1:1:1:1 ratio, approximately.

L. Synthesis of Valdecoxib and Valdecoxib Ester Analog.

1-phenylbut-2-yn-1-one (SI-5) was prepared according to a literatureprocedure.¹⁵ To a flame-dried 100 mL round bottom flask equipped withstir bar under N₂ atmosphere was added FeCl₃ (162 mg, 1.00 mmol, 0.10equiv). The flask was evacuated and purged with N₂ in three cycles. Thereaction flask was cooled to 0° C. in an ice-water bath. Acid chlorideSI-1a (1.16 mL, 10.0 mmol, 1.00 equiv), trimethylsilylpropyne (2.22 mL,15.0 mmol, 1.50 equiv), and CH₃NO₂ (20.0 mL) were added to the reactionflask at 0° C. under N₂ atmosphere. The reaction mixture was stirred at0° C. for 6 h. The reaction mixture was then allowed to warm to 25° C.The suspension was filtered through a Celite plug (ca. 0.5 mL), andrinsed with dichloromethane (3×5 mL). The crude reaction mixture wasconcentrated in vacuo, purified by silica gel flash columnchromatography (5% EtOAc in hexanes) to afford SI-5 as a yellow oil(0.867 g, 60% isolated yield). TLC (20% EtOAc/hexanes): R_(f)=0.42,visualized by UV absorbance. ¹H NMR (CDCl₃, 500 MHz) b: 8.14 (d, J=7.5Hz, 2H), 7.60 (t, J=7.5 Hz, 1H), 7.48 (t, J=8.0 Hz, 2H), 2.16 (s, 3H).This spectrum is in agreement with previously reported spectral data.¹⁵

(Z)-1-phenylbut-2-yn-1-one oxime (22) was prepared according to aliterature procedure.⁹ A 50 mL round bottom flask was charged withH₂NOH.HCl (2.2 equiv), Na₂SO₄ (3.0 equiv), and a stir bar. The solidswere suspended in MeOH (10 mL). Pyridine (4.0 equiv) and then ketoneSI-5 (1.0 equiv) were added. The reaction was stirred at roomtemperature until the starting material was consumed completely, asshown by TLC. The reaction was quenched with 15 mL DI water andextracted with EtOAc (3×15 mL). The combined organic layers were washedwith brine (15 mL), dried over MgSO₄, filtered, and concentrated invacuo. The crude was purified by silica gel flash column chromatographyusing a stepwise gradient from 5% to 10% EtOAc in hexanes.Product-containing fractions were combined and concentrated in vacuo toafford 22 as a yellow solid (111 mg, 12% isolated yield). TLC (20%EtOAc/hexanes): R_(f)=0.19, visualized by UV absorbance. ¹H NMR(d₈-toluene, 500 MHz): δ 9.03 (s, 1H), 7.95-7.93 (m, 2H), 7.11-7.06 (m,3H), 1.61 (s, 3H). ¹³C NMR (d₈-toluene, 125 MHz): δ 142.1, 134.4, 129.7,128.6, 126.9, 100.5, 71.0, 4.1. HRMS (ESI+) m/z calcd for C₁₀H₉NO([M+Na]⁺) 182.0582, found 182.0579.

Pinacol boronate (23). In a N₂-filled glovebox, alkynyloxime 22 (31.8mg, 0.200 mmol, 1.00 equiv) was dissolved in 0.6 mL toluene in a 4-dramvial equipped with stir bar. Catecholborane (21.4 μL, 0.200 mmol, 1.00equiv) was added via gastight syringe to the solution above. Theresulting solution was allowed to stir at room temperature for 0.5 h.The catalyst IPrAuTFA (3.5 mg, 0.0050 mmol, 2.5 mol %) was dissolved in0.4 mL toluene and transferred via syringe to the solution above in acapped vial and the resulting suspension was stirred in a pre-heated 50°C. copper shot heating bath for 6 h. The reaction mixture was thencooled to room temperature and a solution of PPh₃ (2.6 mg, 0.010 mmol,5.0 mol %) in toluene (1.2 mL) was added. The resulting suspension wasstirred for 20 h at room temperature in order to quench IPrAuTFA beforeproceeding.

Pinacol (70.8 mg, 0.600 mmol, 3.00 equiv) was dissolved in anhydrousEt₃N (0.42 mL, 3.0 mmol, 15.0 equiv). The resulting solution was addedto the quenched reaction mixture, and the resulting suspension wasstirred at 25° C. for 1 h. The reaction mixture was then removed fromthe glovebox. Volatiles were removed in vacuo. The resulting light brownoil was purified by silica gel chromatography using an elution gradientfrom 100% hexanes to 100% CH₂Cl₂. Solvents were removed in vacuo toafford the desired pinacol boronate 23 as white solid (40.5 mg, 71%isolated yield). TLC (40% CH₂Cl₂/hexanes): R_(f)=0.08, visualized by UVabsorbance. ¹H NMR (CDCl₃, 600 MHz): δ 7.83-7.81 (m, 2H), 7.43-7.39 (m,3H), 2.61 (s, 3H), 1.30 (s, 12H). This spectrum is in agreement withpreviously reported spectral data.¹²

Valdecoxib (25) was prepared according to a literature procedure, butwith using building block 14 from our method.¹²³ To a flame-dried 10 mLround bottom flask equipped with stir bar under N₂ atmosphere was addedpinacol boronate 23 (54.4 mg, 0.191 mmol, 1.00 equiv), PdCl₂(dppf).DCM(15.5 mg, 0.0190 mmol, 0.100 equiv), K₃PO₄ (122 mg, 0.574 mmol, 3.00equiv), sulfonamide 24 (90.2 mg, 0.382 mmol, 2.00 equiv), and degasseddioxane (1.2 mL). The reaction mixture was stirred at 85° C. for 21 h.The reaction mixture was allowed to cool to 25° C., quenched by DI water(10 mL). The aqueous layer was extracted with dichloromethane (3×20 mL).The combined organic layer was washed with brine (20 mL), dried overMgSO₄, filtered, and concentrated in vacuo. The crude was purified bysilica gel flash column chromatography using an elution gradient from30% to 40% EtOAc in hexanes to afford 25 as a light yellow solid (37.4mg, 62% isolated yield). TLC (40% EtOAc/hexanes): R_(f)=0.14, visualizedby UV absorbance. ¹H NMR (CD₃OD, 600 MHz) b: 7.91 (d, J=8.4 Hz, 2H),7.44-7.35 (m, 7H), 4.84 (s, 2H), 2.49 (s, 3H). This spectrum is inagreement with previously reported spectral data.¹²

Valdecoxib ester analog (26) was prepared according to a literatureprocedure,¹² using building block 4k from our method. To a flame-dried10 mL round bottom flask equipped with stir bar under N₂ atmosphere wasadded pinacol boronate 4k (59.0 mg, 0.159 mmol, 1.00 equiv),PdCl₂(dppf).DCM (13.0 mg, 0.0159 mmol, 0.100 equiv), K₃PO₄ (101 mg,0.477 mmol, 3.00 equiv), sulfonamide 24 (75.0 mg, 0.318 mmol, 2.00equiv), and degassed dioxane (1.20 mL). The reaction mixture was stirredat 90° C. for 46 h. The reaction mixture was allowed to cool to 25° C.,quenched by DI water (10 mL). The aqueous layer was extracted withdichloromethane (3×20 mL). The combined organic layer was washed withbrine (20 mL), dried over MgSO₄, filtered, and concentrated in vacuo.The crude was purified by silica gel flash column chromatography usingan elution gradient from 30% to 40% EtOAc in hexanes to afford 26 as awhite solid (47.1 mg, 74% isolated yield). TLC (40% EtOAc/hexanes):R_(f)=0.14, visualized by UV absorbance. ¹H NMR (d₆-acetone, 500 MHz) b:7.93-7.91 (m, 2H), 7.45-7.36 (m, 7H), 6.70 (bs, 1H), 3.81 (bs, 1H), 3.57(s, 3H), 2.94-2.91 (m, 4H), 2.40 (t, J=7.0 Hz, 2H). ¹³C NMR (d₆-acetone,125 MHz): δ 173.3, 170.8, 161.6, 144.3, 134.8, 131.2, 130.3, 129.8,129.4, 129.1, 127.2, 115.5, 51.6, 33.2, 25.4, 23.5. HRMS (ESI+) m/zcalcd for C₂₀H₂₀N₂O₅S ([M+Na]⁺) 423.0991, found 423.0987.

L. Gram-Scale Preparation of 4a

The gram-scale uncatalyzed oxyboration reaction was conducted in aN₂-filled glovebox. A flame-dried 100-mL round bottom flask with astirbar was charged with oxime 1a (1.63 g, 8.10 mmol, 1.00 equiv).Anhydrous toluene (15.0 mL) was added. To the resulting rapidly stirringsuspension was added catecholborane (0.867 mL, 8.10 mmol, 1.00 equiv)via gastight syringe, and allowed to stir at room temperature for 30min. The round bottom flask was heated in a preheated copper shotheating bath at 110° C. until full consumption of starting materials wasachieved (12 days).

Pinacol (2.87 g, 24.3 mmol, 3.00 equiv) was dissolved in anhydrous Et₃N(3.37 mL, 24.3 mmol, 3.00 equiv). The resulting solution was added tothe quenched reaction mixture, and the resulting suspension was stirredat 25° C. for 2 h. The reaction mixture was then removed from theglovebox. Volatiles were removed in vacuo. The resulting light brown oilwas purified by silica gel chromatography using an elution gradient from100% hexanes to 100% CH₂Cl₂. Solvents were removed in vacuo to affordthe desired pinacol boronate 4a as a light yellow oil (1.70 g, 64%isolated yield). Spectral data were identical to those previouslyobtained for this compound.

REFERENCES

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Example 5

This communication demonstrates the first catalytic aminoboration of C—Cπ bonds by B—N σ bonds and its application to the synthesis of3-borylated indoles. The regiochemistry and broad functional groupcompatibility of this addition reaction enable substitution patternsthat are incompatible with major competing technologies. Thisaminoboration reaction effects the formation of C—B and C—N bonds in asingle step from aminoboronic esters, which are simple startingmaterials available on the gram scale. This reaction generatessynthetically valuable N-heterocyclic organoboron compounds as potentialbuilding blocks for drug discovery. The working mechanistic hypothesisinvolves a bifunctional Lewis acid/base catalysis strategy involving thecombination of a carbophilic gold cation and a trifluoroacetate anionthat activate the C—C π bond and the B—N σ bond simultaneously

Discussion:

Boron-element additions to unsaturated compounds have played a pivotalrole in organic synthesis since the discovery of hydroboration by Hurd¹and Brown.² These transformations provide a route to syntheticallyvaluable organoboron compounds that are widely used as versatilereagents in carbon-carbon and carbon-heteroatom bond forming reactions,such as the Suzuki-Miyaura reaction³ and Chan-Lam cross-coupling⁴. Thus,transition metal-catalyzed 1,2-addition of boron-element bonds (B-E,where E=H,⁵⁻⁸ B,⁸⁻¹⁰ C,¹¹⁻¹³ Si,^(8,14,15) Sn,^(8,16) S,¹⁷ Cl,¹⁸ Br,¹⁹I¹⁹) to C—C multiple bonds have received significant attention (FIG.5.1A). In most of these methods, the B-E single bonds are activated viaoxidative addition to a low-valent late transition metal center (e.g.,Rh, Ni, Pd, Pt) or via σ-bond metathesis with a late-metal catalyst(e.g., Cu²⁰) prior to insertion across alkynes. Given that amines arepresent in 85% of all pharmaceutical compounds, it is striking that thecorresponding addition chemistry with B—N bonds has not been developedfor synthetic applications; possibly because the relatively highstrength of the B—N σ bond prevented application of existing mechanisticstrategies. We herein realize this aminoboration reaction by employing adifferent mechanistic strategy: activation of the C—C π bond—the otherpartner in the reaction—with a carbophilic Lewis acid (FIG. 5.1C). Thisreaction employs starting materials containing B—N σ bonds that arereadily available on the gram scale from their corresponding amines andcommercially available B-chlorocatecholborane. It generates 3-borylatedindoles via unique bond disconnections as potential building blocks fordrug discovery, and it is orthogonal to major competing technologies asit tolerates aryl halides, nitriles, and esters.

The resistance of B—N σ bonds to react with unactivated C—C π bonds isnot surprising given that aminoboranes (R₂B—NR₂) are known to haveisostructural and isoelectronic relationship to alkenes due to then-interaction between nitrogen's lone pair and boron's empty porbital.^(21,22) Resultantly, prior work on aminoboration was limited tothe addition of B—N bonds to polarized C-heteroatom π bonds thatincluded isocyanate,²³⁻²⁵ isothiocyanate,²³ and carbodiimide.²⁶ Such anapproach is less synthetically useful, however, as the resultingB-heteroatom bond formed in those transformations are usually hydrolyzedand the boryl component lost at the end of the reaction.²³⁻²⁶ To ourknowledge, the only reported example of aminoboration of a C—C multiplebond with a B—N σ bond is the [4+2] cycloaddition of a straineddiazadiboretidine with dimethylacetylenedicarboxylate, which leads to aheterocycle of limited synthetic utility for downstreamfunctionalization (FIG. 5.1B).²⁷ More recently, a formal aminoborationof alkenes was reported using a Cu-catalyzed borylation withbis(pinacolato)diboron (pinB-Bpin) followed by an electrophilicamination using O-benzoyl-N,N-dialkylhydroxylamine (R₂N—OBz).²⁸⁻³²Furthermore, despite a recent development on the addition chemistryinvolving the analogous B—P bond,³³ the catalytic aminoboration ofalkynes with the B—N bond was unknown prior to this work.

Indoles are privileged scaffolds found in numerous biologically activemolecules and employed in medicinal chemistry,³⁴⁻³⁷ including recenttherapeutic leads.³⁸ Thus, the construction of indole ring system wastargeted (initial development, Table 1), which would give access to3-borylated indoles as potential building blocks for drug discovery.During initial reaction identification, the requisite B—N bond ofaminoboronic ester 2 was formed from the reaction of 2-alkynylaniline 1and commercially available catecholborane in d₈-toluene with heating andthe release of H₂. The formation of this B—N bond was monitored andconfirmed by ¹¹B NMR spectroscopy, at δ ˜26 ppm³⁹ with concurrentdisappearance of the signal from catecholborane at δ 28.7 ppm.

Table 1, Example 5. Initial Development of Aminoboration

entry substrate R conditions yield (%)^(a) 3 1 1a H  50° C., 15.5 h0^(b) 2 1b CH₂Ph  80° C., 5 h n.r.^(c) 3 1b CH₂Ph 110° C., 17 h 55 4 1cTs  50° C., 4 h n.r.^(c) 5 1c Ts  80° C., 20 h 64^(d) 6 1d Mbs  80° C.,20 h 66 ^(a)Isolated yield of the Bpin product. ^(b)Only2-phenyl-1H-indole was obtained in 69% yield. ^(c)No reaction observedas monitored by ¹H NMR spectroscopy. ^(d)Average of two runs.

When the aminoboronic ester 2a (Table 1, entry 1), derived from primaryaniline 1a, was treated with IPrAuTFA catalyst⁴⁰ and heated at 50° C.,the desired 3-borylated indole 3 was not obtained. Instead, only2-phenyl-1H-indole was isolated in 69% yield, suggesting thatprotodeborylation occurs in the presence of an N—H bond. To circumventthis problem, secondary anilines 1b-1d (entries 2-6) were examined foraminoboration. Gratifyingly, the use of N-benzyl substituent providedthe first aminoboration reactivity in 55% yield (entry 3), but hightemperatures of 110° C. were required. Examination of N-sulfonylsubstituents, tosyl (entry 4 and 5) and 4-methoxybenzenesulfonyl (Mbs,entry 6), showed that the reaction can be accomplished at the lowertemperature of 80° C. The moderate yields obtained under the conditionsof initial reaction development are attributed to the degradation ofcatecholborane (HBcat) into B₂cat₃ via catechol ligand redistribution,⁴¹observed by a signal at δ 23.1 ppm in the ¹¹B spectrum, as well asunreacted 1 remaining from the first aminolysis step with HBcat.

Switching to aminolysis of commercially available B-chlorocatecholborane(CIBcat) by 2-alkynlaniline 1 provided a solution for easily assemblingthe requisite B—N bond at room temperature within an hour usingtriethylamine as a base to trap the released HCl byproduct (eq1).^(42,43) In situ formed 2 does not undergo cyclization in the absenceof the IPrAuTFA catalyst; for example, substrate 2d remains unreactedwith the B—N bond intact when heated to 110° C. in d₈-toluene for 20 hin the absence of a catalyst.

Our aminoboration strategy allows access to 3-borylated indoles withcomplementary regiochemistry and with functional groups that areincompatible with conventional routes or recent synthetic efforts (Chart1). Alternative iridium-catalyzed C—H activation routes areregioselective for borylation at the 2-⁴⁴ or 7-positions^(45,46) ofindoles. Traditional metal-halogen exchange/borylation strategy⁴⁷ ofaryl halides with magnesium or o-lithiation/borylation⁴⁸ of arenes withorganolithium reagents are unable to tolerate aryl bromides, nitriles,esters, and other metalation-sensitive heterocycles. Palladium-catalyzedMiyaura borylation⁴⁹ of aryl halides or borylative cyclization⁵⁰ of2-alkynylanilines are also incompatible for the synthesis brominatedindole 3-boronic esters due to the potential oxidative addition of Pdinto Ar—Br bond.

Chart 1, Example 5. Aminoboration Scope of 3-Borylated Indoles^(a) withFunctional Groups Incompatible with Competing Metalation orPd(0)-Catalyzed Technologies Shown in Blue

The aminoboration reaction is compatible with a variety of thesepotentially sensitive functional groups. Compounds with these functionalgroups are shown in blue in Chart 1. Pharmaceutically relevantthiophenes (3e), aryl bromides (3g and 3l), nitriles (3h), esters (3i)are tolerated by this method, as are alkenes (3j) and silyl-protectedalcohols (3m). For bulkier substituents at R², o-substituted aryl (31)and OTBDPS (3m), increased temperatures of 110° C. were required toinduce the cyclization. Pharmaceutically relevant⁵¹ 1,3-benzodioxoles(3f) also can be tolerated in this transformation.

Due to the challenge of achieving the required functional grouptolerance with alternative metalation and palladium(0)-catalyzedmethods, borylated bromoindoles previously were made via routes withhighly toxic mercury acetate.^(38,52) For example, in the totalsynthesis of dragmacidin D by Stoltz and coworkers, a tosylatedbromoindole was borylated at the 3-position using mercuration withHg(OAc)₂ followed by Hg/B exchange with BH₃.⁵² Recent industrialpharmaceutical leads have also been synthesized by mercuration routes inorder generate these borylated bromoindoles.³⁸ In contrast, thefunctional group tolerance of the aminoboration method provides amercury-free route to the synthesis of borylated bromoindoles (e.g.,3g).

The aminoboration reaction of 2-alkynylanilines can be easily run on thegram scale (Scheme 5A, Example 5). The scalability of thishalide-tolerant aminoboration transformation demonstrates its syntheticutility and allows for generation of quantities suitable for multistepsynthesis for downstream manipulation of the C—Br and C—B bonds incross-coupling reactions.^(3,4) The solid-state molecular structure of3g, obtained from single-crystal X-ray diffraction analysis, verifiesthe structure of the aminoborylated product arising from anti1,2-addition of B—N bond across alkynes.

The employment of bromine-containing 3-borylated indole 3g in sequentialSuzuki cross-coupling reactions highlights this downstream syntheticutility (Scheme 5B, Example 5). The C—B bond of 3g accesses a selectivecross-coupling with an aryl iodide at room temperature to generate a newC—C bond,⁵² while maintaining the C—Br bond intact, to affordfunctionalized indole 4. The Ar—Br bond of 4 is available for a secondcross-coupling with organoboronic acid derivatives, and here we furtherdemonstrate the synthetic utility of 3-borylated indole 3d as a buildingblock for C—C bond formation to construct biindole 5. Biindole scaffoldshave reported biological activities,⁵³⁻⁵⁵ and this aminoborationfacilitates access to such structures.

The synthetic utility of aminoboration is not limited to indolescaffolds and has potential for applications in the synthesis of otherN-heterocyclic organoboron compounds (Scheme 5C, Example 5). When asimple amine 6, prepared from commercially available homopropargylamine, is subjected to standard aminoboration conditions, 3-borylateddihydropyrrole 8a can be synthesized. The protodeborylated product 8b isthe major byproduct, possibly due to a source of an acidic proton fromthe terminal alkyne of 7. This preliminary result demonstrates that arigid backbone to aid cyclization and a gain of product aromaticity arenot absolute requirements for the aminoboration reactivity.

Numerous examples of Lewis acidic gold-mediated cyclization of2-alkynylanilines exist for the synthesis of indole derivatives,⁵⁶ butnot for the installation of boron on the indole backbone for downstreamreactivity. Based on the known carbophilicity of gold^(56,57) and ourprevious report on bifunctional catalysis on alkoxyboration of alkynesinvolving B—O bond activation,⁵⁸ we propose the catalytic cycle shown inScheme 5D, Example 5. The potentially bifunctional Lewis acidic/basiccatalyst IPrAuTFA and substrate 2d associate to generate intermediate 9containing a tetracoordinate borate. Simultaneous B—N bond activationand cyclization of 9 releases organogold intermediate 10 andB-(trifluoroacetyl)catecholborane. The presence of proposedintermediates is supported by the detection of neutral organogold 10 inthe reaction mixture by HRMS prior to completion of the reaction. Next,organogold species 10 and B-(trifluoroacetyl)catecholborane undergoAu-to-B transmetalation⁵⁹ to furnish the 3-borylated indole product3d-Bcat and regenerate the IPrAuTFA catalyst. This reaction manifold ismechanistically distinct from the previous metal-catalyzed boron-elementbond addition routes that proceed through metal-mediated breaking of theB-element bond through oxidative addition or a bond metathesis.

This reaction displays a notable dependence on the presence of thesodium trifluoroacetate additive. Optimal conditions occurred with 5 mol% IPrAuTFA catalyst and 20 mol % sodium trifluoroacetate additive (usingeq 1, in Chart 1) and not simply with the IPrAuTFA catalyst alone (inTable 1). No reaction occurred when aminoboronic ester 2, generated fromthe route (eq 1) using CIBcat and NEt₃, was heated to 110° C. ind₈-toluene for 20 h using 2.5 mol % IPrAuTFA catalyst in the absence ofadded sodium trifluoroacetate.

The added sodium trifluoroacetate may overcome catalyst inhibition fromtrace HNEt₃CI leftover during the preparation of 2 via the optimizedchlorocatecholborate route.⁶⁰ In summary, we have developed the firstcatalytic aminoboration reaction that adds B—N σ bonds across C—C πbonds. We have shown that the easily generated but rather unreactive B—Nσ bond can be used for this addition reaction, thereby providing a newbond disconnection strategy for the efficient construction of indolebuilding blocks for potential applications in drug discovery. The use ofcarbophilic gold catalyst and mildly basic trifluoroacetate providestolerance of functional groups that are either incompatible with ordifficult to access using existing methods. Ongoing work focuses on thedevelopment aminoboration reactivity for the synthesis other compoundclasses.

REFERENCES FOR EXAMPLE 5

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It should be noted that ratios, concentrations, amounts, and othernumerical data may be expressed herein in a range format. It is to beunderstood that such a range format is used for convenience and brevity,and thus, should be interpreted in a flexible manner to include not onlythe numerical values explicitly recited as the limits of the range, butalso to include all the individual numerical values or sub-rangesencompassed within that range as if each numerical value and sub-rangeis explicitly recited. To illustrate, a concentration range of “about0.1% to about 5%” should be interpreted to include not only theexplicitly recited concentration of about 0.1 wt % to about 5 wt %, butalso include individual concentrations (e.g., 1%, 2%, 3%, and 4%) andthe sub-ranges (e.g., 0.5%, 1.1%, 2.2%, 3.3%, and 4.4%) within theindicated range. In an embodiment, the term “about” can includetraditional rounding according to significant figures of the numericalvalue. In addition, the phrase “about ‘x’ to ‘y’” includes “about ‘x’ toabout ‘y’”.

It should be emphasized that the above-described embodiments of thepresent disclosure are merely possible examples of implementations, andare set forth only for a clear understanding of the principles of thedisclosure. Many variations and modifications may be made to theabove-described embodiments of the disclosure without departingsubstantially from the spirit and principles of the disclosure. All suchmodifications and variations are intended to be included herein withinthe scope of this disclosure.

We claim at least the following:
 1. A composition, comprising: acompound having a structure selected from the group consisting of:

wherein [B] is BX² _((1 or 2)), where X² for BX² is independentlyselected from: catecholate, pinacolate, ethylene glycolate,1,3-propanediolate, N-methyliminodiacetate, 2,2′-azanediyldiethanolate,fluoride, chloride, bromide, hydrogen, hydroxide, acetate,9-Borabicyclo[3.3.1]nonane (9-BBN), diisopinocampheyl (Ipc), or1,8-diaminonaphthalene, each of which can be substituted orunsubstituted; wherein each of R¹, R², R³, R⁴, R⁵, and R⁷ isindependently selected from: H, a carbonyl functional group (substitutedor unsubstituted), a carbocycle group (substituted or unsubstituted), aheterocycle (substituted or unsubstituted), a halide, an alkyl group(cyclic or acyclic; substituted or unsubstituted), an alkenyl group(cyclic or acyclic; substituted or unsubstituted), CF₃, CN, NO₂, an arylgroup (substituted or unsubstituted), a heteroaryl group (substituted orunsubstituted), a sulfonyl group, a boryl group, an ether group, athioether group, a silyl group, an ester group, an amide group, analkoxy group, a thiol group, an alcohol group, or an amine group; andwherein a “curved line” between R groups represents a carbon chain or ahetero carbon chain; wherein X¹ is selected from the group consistingof: O, NR, S, or CR¹R², where each of R, R¹, R² for X¹ is independentlyselected from: H, a carbonyl functional group, a carboxy group, acarbocycle group, a heterocycle, a halide, or an alkyl group, each ofwhich is optionally substituted or unsubstituted; and wherein X² and X³are independently selected from the group consisting of: O, S, or—C(O)O.
 2. A method of making an organoboron compound, comprising areaction described by one of the following schemes:

wherein [B] and (B′) are each BX² _((1 or 2)), where X² canindependently selected from: catecholate, pinacolate, ethyleneglycolate, 1,3-propanediolate, N-methyliminodiacetate,2,2′-azanediyldiethanolate, fluoride, chloride, bromide, hydrogen,hydroxide, acetate, 9-Borabicyclo[3.3.1]nonane (9-BBN),diisopinocampheyl (Ipc), or 1,8-diaminonaphthalene, each of which can besubstituted or unsubstituted; wherein X of [B]—X is selected from thegroup consisting of: H, a halide, acetoxy (OAc), trifluoroacetate (TFA),tosylate (OTs), mesylate (OMs), or triflate (OTf); wherein each of R¹,R², R³, R⁴, R⁵, R⁶, and R⁷ is independently selected from: H, a carbonylfunctional group (substituted or unsubstituted), a carbocycle group(substituted or unsubstituted), a heterocycle (substituted orunsubstituted), a halide, an alkyl group (cyclic or acyclic; substitutedor unsubstituted), an alkenyl group (cyclic or acyclic; substituted orunsubstituted), CF₃, CN, NO₂, an aryl group (substituted orunsubstituted), a heteroaryl group (substituted or unsubstituted), asulfonyl group, a boryl group, an ether group, a thioether group, asilyl group, an ester group, an amide group, an alkoxy group, a thiolgroup, an alcohol group, or an amine group; wherein a “curved line”between R groups represents a carbon chain or a hetero carbon chain;wherein X¹ is selected from the group consisting of: O, NR, S, or CR¹R²,where each of R, R¹, R² for X¹ is independently selected from: H, acarbonyl functional group, a carboxy functional group, a carbocyclegroup, a heterocycle, a halide, or an alkyl group, each of which isoptionally substituted or unsubstituted; wherein X² and X³ areindependently selected from the group consisting of: O, S, or —C(O)O;and wherein the reagent in each Scheme is reacted with a salt of BX² toform the organoboron compound(s) shown in each Scheme.